Hubbry Logo
MetastasisMetastasisMain
Open search
Metastasis
Community hub
Metastasis
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Contribute something
Metastasis
Metastasis
Metastasis
View on Wikipedia
from Wikipedia
Squamous cell carcinoma occluding bronchus with metastasis to adjacent lymph node.

Metastasis
Other namesMetastatic disease
Illustration showing hematogenous metastasis
Pronunciation
SpecialtyOncology

Metastasis is the spread of a pathogenic agent from an initial or primary site to a different or secondary site within the host's body;[1] the term is typically used when referring to metastasis by a cancerous tumor.[2] The newly pathological sites, then, are metastases (mets).[3][4] It is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues.[5]

Cancer occurs after cells are genetically altered to proliferate rapidly and indefinitely. This uncontrolled proliferation by mitosis produces a primary heterogeneic tumour. The cells which constitute the tumor eventually undergo metaplasia, followed by dysplasia then anaplasia, resulting in a malignant phenotype. This malignancy allows for invasion into the circulation, followed by invasion to a second site for tumorigenesis.

Some cancer cells, known as circulating tumor cells (CTCs), are able to penetrate the walls of lymphatic or blood vessels, and circulate through the bloodstream to other sites and tissues in the body.[6] This process, known respectively as lymphatic or hematogenous spread, allows not only single cells but also groups of cells, or CTC clusters, to travel. Evidence suggests that CTC clusters may retain their multicellular configuration throughout metastasis, enhancing their ability to establish secondary tumors.[7] This perspective aligns with the cancer exodus hypothesis, which posits that maintaining this cluster structure contributes to a higher metastatic potential. Metastasis is one of the hallmarks of cancer, distinguishing it from benign tumors.[8] Most cancers can metastasize, although in varying degrees. Basal cell carcinoma for example rarely metastasizes.[8]

When tumor cells metastasize, the new tumor is called a secondary or metastatic tumor, and its cells are similar to those in the original or primary tumor.[9] This means that if breast cancer metastasizes to the lungs, the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells. The tumor in the lung is then called metastatic breast cancer, not lung cancer. Metastasis is a key element in cancer staging systems such as the TNM staging system, where it represents the "M". In overall stage grouping, metastasis places a cancer in Stage IV. The possibilities of curative treatment are greatly reduced, or often entirely removed when a cancer has metastasized.

Signs and symptoms

[edit]
Cut surface of a liver showing multiple paler metastatic nodules originating from pancreatic cancer

Initially, nearby lymph nodes are struck early.[10] The lungs, liver, brain, and bones are the most common metastasis locations from solid tumors.[10]

Although advanced cancer may cause pain, it is often not the first symptom.

Some patients, however, do not show any symptoms.[10] When the organ gets a metastatic disease it begins to shrink until its lymph nodes burst, or undergo lysis.

Pathophysiology

[edit]

Metastatic tumors are very common in the late stages of cancer. The spread of metastasis may occur via the blood or the lymphatics or through both routes. The most common sites of metastases are the lungs, liver, brain, and the bones.[10]

Currently, three main theories have been proposed to explain the metastatic pathway of cancer: the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) hypothesis, the cancer stem cell hypothesis, and the macrophage–cancer cell fusion hybrid hypothesis. Some new hypotheses were suggested as well, i.e., under the effect of particular biochemical and/or physical stressors, cancer cells can undergo nuclear expulsion with subsequent macrophage engulfment and fusion, with the formation of cancer fusion cells (CFCs).[11] Understanding the enigma of cancer cell spread to distant sites, which accounts for over 90% of cancer-related deaths, necessitates comprehensive investigation. Key outstanding questions revolve around the survival and migration of cancer cells, such as the nucleus, as they face challenges in passage through capillary valves and hydrodynamic shear forces in the circulation system, making CTCs an unlikely source of metastasis. Moreover, understanding how cancer cells adapt to the metastatic niche and remain dormant (tumor dormancy) for extended periods presents difficult questions that require further investigation.[11]

Factors involved

[edit]

Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension. To do so, malignant cells break away from the primary tumor and attach to and degrade proteins that make up the surrounding extracellular matrix (ECM), which separates the tumor from adjoining tissues. By degrading these proteins, cancer cells are able to breach the ECM and escape. The location of the metastases is not always random, with different types of cancer tending to spread to particular organs and tissues at a rate that is higher than expected by statistical chance alone.[12] Breast cancer, for example, tends to metastasize to the bones and lungs. This specificity seems to be mediated by soluble signal molecules such as chemokines[13] and transforming growth factor beta.[14] The body resists metastasis by a variety of mechanisms through the actions of a class of proteins known as metastasis suppressors, of which about a dozen are known.[15]

Human cells exhibit different kinds of motion: collective motility, mesenchymal-type movement, and amoeboid movement. Cancer cells often opportunistically switch between different kinds of motion. Some cancer researchers hope to find treatments that can stop or at least slow down the spread of cancer by somehow blocking some necessary step in one or more kinds of motion.[16][17]

All steps of the metastatic cascade involve a number of physical processes. Cell migration requires the generation of forces, and when cancer cells transmigrate through the vasculature, this requires physical gaps in the blood vessels to form.[18] Besides forces, the regulation of various types of cell-cell and cell-matrix adhesions is crucial during metastasis.[citation needed]

The metastatic steps are critically regulated by various cell types, including the blood vessel cells (endothelial cells), immune cells or stromal cells. The growth of a new network of blood vessels, called tumor angiogenesis,[19] is a crucial hallmark of cancer. It has therefore been suggested that angiogenesis inhibitors would prevent the growth of metastases.[8] Endothelial progenitor cells have been shown to have a strong influence on metastasis and angiogenesis.[20][21] Endothelial progenitor cells are important in tumor growth, angiogenesis and metastasis, and can be marked using the Inhibitor of DNA Binding 1 (ID1). This novel finding meant that investigators gained the ability to track endothelial progenitor cells from the bone marrow to the blood to the tumor-stroma and even incorporated in tumor vasculature. Endothelial progenitor cells incorporated in tumor vasculature suggests that this cell type in blood-vessel development is important in a tumor setting and metastasis. Furthermore, ablation of the endothelial progenitor cells in the bone marrow can lead to a significant decrease in tumor growth and vasculature development. Therefore, endothelial progenitor cells are important in tumor biology and present novel therapeutic targets.[22] The immune system is typically deregulated in cancer and affects many stages of tumor progression, including metastasis.[citation needed]

Epigenetic regulation also plays an important role in the metastatic outgrowth of disseminated tumor cells. Metastases display alterations in histone modifications, such as H3K4-methylation and H3K9-methylation, when compared to matching primary tumors.[23] These epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs.[24]

A recent study shows that PKC-iota promotes melanoma cell invasion by activating Vimentin during EMT. PKC-iota inhibition or knockdown resulted in an increase in E-cadherin and RhoA levels while decreasing total Vimentin, phosphorylated Vimentin (S39) and Par6 in metastatic melanoma cells. These results suggested that PKC-ι is involved in signaling pathways which upregulate EMT in melanoma thereby directly stimulates metastasis.[25]

Recently, a series of high-profile experiments suggests that the co-option of intercellular cross-talk mediated by exosome vesicles is a critical factor involved in all steps of the invasion-metastasis cascade.[26]

Routes

[edit]

Metastasis occurs by the following four routes:

Transcoelomic

[edit]

The spread of a malignancy into body cavities can occur via penetrating the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. For example, ovarian tumors can spread transperitoneally to the surface of the liver.[citation needed]

Lymphatic spread

[edit]

Lymphatic spread allows the transport of tumor cells to regional lymph nodes near the primary tumor and ultimately, to other parts of the body. This is called nodal involvement, positive nodes, or regional disease. "Positive nodes" is a term that would be used by medical specialists to describe regional lymph nodes that tested positive for malignancy. It is common medical practice to test by biopsy at least one lymph node near a tumor site when carrying out surgery to examine or remove a tumor. This lymph node is then called a sentinel lymph node. Lymphatic spread is the most common route of initial metastasis for carcinomas.[8] In contrast, it is uncommon for a sarcoma to metastasize via this route. Localized spread to regional lymph nodes near the primary tumor is not normally counted as a metastasis, although this is a sign of a worse outcome. The lymphatic system does eventually drain from the thoracic duct and right lymphatic duct into the systemic venous system at the venous angle and into the brachiocephalic veins, and therefore these metastatic cells can also eventually spread through the haematogenous route.[citation needed]

Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin

Hematogenous spread

[edit]

This is typical route of metastasis for sarcomas, but it is also the favored route for certain types of carcinoma, such as renal cell carcinoma originating in the kidney and follicular carcinomas of the thyroid. Because of their thinner walls, veins are more frequently invaded than are arteries, and metastasis tends to follow the pattern of venous flow. That is, hematogenous spread often follows distinct patterns depending on the location of the primary tumor. For example, colorectal cancer spreads primarily through the portal vein to the liver.[citation needed]

Canalicular spread

[edit]

Some tumors, especially carcinomas may metastasize along anatomical canalicular spaces. These spaces include for example the bile ducts, the urinary system, the airways and the subarachnoid space. The process is similar to that of transcoelomic spread. However, often it remains unclear whether simultaneously diagnosed tumors of a canalicular system are one metastatic process or in fact independent tumors caused by the same agent (field cancerization).[citation needed]

Organ-specific targets

[edit]
Main sites of metastases for some common cancer types. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases".[27]

There is a propensity for certain tumors to seed in particular organs. This was first discussed as the seed and soil theory by Stephen Paget in 1889.[28] The propensity for a metastatic cell to spread to a particular organ is termed 'organotropism'. For example, prostate cancer usually metastasizes to the bones. In a similar manner, colon cancer has a tendency to metastasize to the liver. Stomach cancer often metastasises to the ovary in women, when it is called a Krukenberg tumor.[citation needed]

According to the seed and soil theory, it is difficult for cancer cells to survive outside their region of origin, so in order to metastasize they must find a location with similar characteristics.[29] For example, breast tumor cells, which gather calcium ions from breast milk, metastasize to bone tissue, where they can gather calcium ions from bone. Malignant melanoma spreads to the brain, presumably because neural tissue and melanocytes arise from the same cell line in the embryo.[30]

In 1928, James Ewing challenged the seed and soil theory, and proposed that metastasis occurs purely by anatomic and mechanical routes. This hypothesis has been recently utilized to suggest several hypotheses about the life cycle of circulating tumor cells (CTCs) and to postulate that the patterns of spread could be better understood through a 'filter and flow' perspective.[31] However, contemporary evidences indicate that the primary tumour may dictate organotropic metastases by inducing the formation of pre-metastatic niches at distant sites, where incoming metastatic cells may engraft and colonise.[26] Specifically, exosome vesicles secreted by tumours have been shown to home to pre-metastatic sites, where they activate pro-metastatic processes such as angiogenesis and modify the immune contexture, so as to foster a favourable microenvironment for secondary tumour growth.[26]

Metastasis and primary cancer

[edit]

It is theorized that metastasis always coincides with a primary cancer, and, as such, is a tumor that started from a cancer cell or cells in another part of the body. However, over 10% of patients presenting to oncology units will have metastases without a primary tumor found. In these cases, doctors refer to the primary tumor as "unknown" or "occult," and the patient is said to have cancer of unknown primary origin (CUP) or unknown primary tumors (UPT).[32] It is estimated that 3% of all cancers are of unknown primary origin.[33] Studies have shown that, if simple questioning does not reveal the cancer's source (coughing up blood—"probably lung", urinating blood—"probably bladder"), complex imaging will not either.[33] In some of these cases a primary tumor may appear later.[citation needed]

The use of immunohistochemistry has permitted pathologists to give an identity to many of these metastases. However, imaging of the indicated area only occasionally reveals a primary. In rare cases (e.g., of melanoma), no primary tumor is found, even on autopsy. It is therefore thought that some primary tumors can regress completely, but leave their metastases behind. In other cases, the tumor might just be too small and/or in an unusual location to be diagnosed.[citation needed]

Diagnosis

[edit]
Pulmonary metastases shown on Chest X-Ray

The cells in a metastatic tumor resemble those in the primary tumor. Once the cancerous tissue is examined under a microscope to determine the cell type, a doctor can usually tell whether that type of cell is normally found in the part of the body from which the tissue sample was taken.[citation needed]

For instance, breast cancer cells look the same whether they are found in the breast or have spread to another part of the body. So, if a tissue sample taken from a tumor in the lung contains cells that look like breast cells, the doctor determines that the lung tumor is a secondary tumor. Still, the determination of the primary tumor can often be very difficult, and the pathologist may have to use several adjuvant techniques, such as immunohistochemistry, FISH (fluorescent in situ hybridization), and others. Despite the use of techniques, in some cases the primary tumor remains unidentified.

Metastatic cancers may be found at the same time as the primary tumor, or months or years later. When a second tumor is found in a patient that has been treated for cancer in the past, it is more often a metastasis than another primary tumor.

It was previously thought that most cancer cells have a low metastatic potential and that there are rare cells that develop the ability to metastasize through the development of somatic mutations.[34] According to this theory, diagnosis of metastatic cancers is only possible after the event of metastasis. Traditional means of diagnosing cancer (e.g. a biopsy) would only investigate a subpopulation of the cancer cells and would very likely not sample from the subpopulation with metastatic potential.[35]

The somatic mutation theory of metastasis development has not been substantiated in human cancers. Rather, it seems that the genetic state of the primary tumor reflects the ability of that cancer to metastasize.[35] Research comparing gene expression between primary and metastatic adenocarcinomas identified a subset of genes whose expression could distinguish primary tumors from metastatic tumors, dubbed a "metastatic signature."[35] Up-regulated genes in the signature include: SNRPF, HNRPAB, DHPS and securin. Actin, myosin and MHC class II down-regulation was also associated with the signature. Additionally, the metastatic-associated expression of these genes was also observed in some primary tumors, indicating that cells with the potential to metastasize could be identified concurrently with diagnosis of the primary tumor.[36] Recent work identified a form of genetic instability in cancer called chromosome instability (CIN) as a driver of metastasis.[37] In aggressive cancer cells, loose DNA fragments from unstable chromosomes spill in the cytosol leading to the chronic activation of innate immune pathways, which are hijacked by cancer cells to spread to distant organs.

Expression of this metastatic signature has been correlated with a poor prognosis and has been shown to be consistent in several types of cancer. Prognosis was shown to be worse for individuals whose primary tumors expressed the metastatic signature.[35] Additionally, the expression of these metastatic-associated genes was shown to apply to other cancer types in addition to adenocarcinoma. Metastases of breast cancer, medulloblastoma and prostate cancer all had similar expression patterns of these metastasis-associated genes.[35]

The identification of this metastasis-associated signature provides promise for identifying cells with metastatic potential within the primary tumor and hope for improving the prognosis of these metastatic-associated cancers. Additionally, identifying the genes whose expression is changed in metastasis offers potential targets to inhibit metastasis.[35]

Management

[edit]

Treatment and survival is determined, to a great extent, by whether or not a cancer remains localized or spreads to other locations in the body. If the cancer metastasizes to other tissues or organs it usually dramatically increases a patient's likelihood of death. Some cancers—such as some forms of leukemia, a cancer of the blood, or malignancies in the brain—can kill without spreading at all.

Once a cancer has metastasized it may still be treated with radiosurgery, chemotherapy, radiation therapy, biological therapy, hormone therapy, surgery, or a combination of these interventions ("multimodal therapy"). The choice of treatment depends on many factors, including the type of primary cancer, the size and location of the metastases, the patient's age and general health, and the types of treatments used previously. In patients diagnosed with CUP it is often still possible to treat the disease even when the primary tumor cannot be located.

Current treatments are rarely able to cure metastatic cancer though some tumors, such as testicular cancer and thyroid cancer, are usually curable.

Palliative care, care aimed at improving the quality of life of people with major illness, has been recommended as part of management programs for metastasis.[38] Results from a systematic review of the literature on radiation therapy for brain metastases found that there is little evidence to inform comparative effectiveness and patient-centered outcomes on quality of life, functional status, and cognitive effects.[39]

Research

[edit]

Although metastasis is widely accepted to be the result of the tumor cells migration, there is a hypothesis saying that some metastases are the result of inflammatory processes by abnormal immune cells.[40] The existence of metastatic cancers in the absence of primary tumors also suggests that metastasis is not always caused by malignant cells that leave primary tumors.[41]

The research done by Sarna's team proved that heavily pigmented melanoma cells have Young's modulus about 4.93, when in non-pigmented ones it was only 0.98.[42] In another experiment they found that elasticity of melanoma cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They showed that there are both pigmented and non-pigmented cells in melanoma tumors, so that they can both be drug-resistant and metastatic.[42]

History

[edit]

The first physician to report the possibility of local metastasis from a primary cancerous source to nearby tissues was Ibn Sina. He described a case of breast cancer and metastatic condition in The Canon of Medicine. His hypothesis was based on clinical course of the patient.[43][44]

In March 2014 researchers discovered the oldest complete example of a human with metastatic cancer. The tumors had developed in a 3,000-year-old skeleton found in 2013 in a tomb in Sudan dating back to 1200 BC. The skeleton was analyzed using radiography and a scanning electron microscope. These findings were published in the Public Library of Science journal.[45][46][47]

Etymology

[edit]

Metastasis is an Ancient Greek word (μετάστασις) meaning "displacement", from μετά, meta, "next", and στάσις, stasis, "placement".

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Metastasis

View on Grokipedia
from Grokipedia
Metastasis is the process by which cancer cells detach from a , invade surrounding tissues, enter the bloodstream or , travel to distant sites, and establish secondary tumors in other organs or parts of the body. This spread, known as the metastatic cascade, transforms localized cancer into a and is the primary cause of death in cancer patients, responsible for over 90% of cancer-related deaths from solid tumors. The metastatic process unfolds in sequential steps: cancer cells first invade nearby normal tissue by breaking through the ; they then enter or vessels through a process called intravasation; surviving cells circulate and evade immune detection; upon reaching a distant site, they exit the vessels via ; finally, they proliferate to form micrometastases that grow into detectable tumors, often by inducing new formation for nourishment. Most circulating cancer cells die during transit due to harsh circulatory conditions and immune attacks, but a small fraction—sometimes remaining dormant for years—successfully colonizes new locations. Common metastatic sites vary by the primary cancer type, with frequent destinations including the lungs, liver, bones, and ; for instance, often spreads to bones or the , while preferentially targets the liver and lungs. Metastatic tumors retain the name and histological features of the original cancer, such as metastatic referring to lung-origin cells in another organ, regardless of the secondary site. This stage of disease, typically classified as stage IV, significantly worsens and shifts treatment goals toward disease control, symptom relief, and extending survival rather than cure.

Clinical Aspects

Signs and Symptoms

Metastatic often presents with symptoms distinct from those of the , as they arise from the involvement of distant organs rather than the original site of cancer origin. For instance, while a primary tumor may cause localized pain or a palpable mass in the , metastasis to the bones can lead to severe, persistent or pathological fractures due to weakened skeletal structure. Similarly, lung metastases may manifest as , , or , contrasting with symptoms from a primary lung tumor that might initially present as a persistent without systemic spread. These site-specific symptoms highlight the advanced nature of the , often emerging when cancer has progressed to stage IV. Liver involvement in metastasis commonly results in jaundice, abdominal swelling, bloating, or early satiety, which differ from primary liver cancer symptoms that may include right upper quadrant pain without the yellowish skin discoloration typical of biliary obstruction from secondary tumors. Brain metastases can cause neurological deficits such as headaches, seizures, , vision changes, or motor impairments, setting them apart from primary brain tumors that might present with more focal neurological signs depending on location. Systemic effects like unintentional , profound , and further underscore the metastatic process, as these paraneoplastic phenomena reflect the body's response to widespread tumor burden rather than isolated primary growth. Paraneoplastic syndromes associated with metastasis include hypercalcemia, often from bone metastases in cancers like or , leading to symptoms of , nausea, and altered mental status due to elevated calcium levels from tumor-secreted parathyroid hormone-related peptide. , characterized by severe muscle wasting and anorexia, is another systemic effect prevalent in advanced metastatic stages, driven by inflammatory cytokines from the tumor. These symptoms significantly impair , with complications like metastatic spinal cord compression—common in vertebral metastases—potentially causing , limb , , and even if untreated, often requiring urgent intervention to preserve mobility. Overall, such manifestations signal advanced disease and necessitate palliative measures to alleviate suffering and maintain function.

Diagnosis

Diagnosis of metastasis typically begins with a clinical suspicion based on symptoms or findings from the evaluation, prompting the use of and to confirm spread. Various modalities help identify metastatic sites, differentiate them from primary lesions, and assess extent, guiding treatment planning. Imaging techniques are fundamental for detecting metastatic involvement across organs. Computed tomography (CT) scans provide detailed cross-sectional images to identify enlarged lymph nodes or masses in the chest, , or , commonly used for staging solid tumors like or . (MRI) excels in evaluating , , and soft tissue metastases due to its superior contrast resolution, often preferred for spinal or hepatic spread. Positron emission tomography (PET) scans, frequently combined with CT (PET-CT), detect metabolically active lesions by tracing glucose uptake, enhancing sensitivity for distant metastases in cancers such as or . serves as an accessible initial tool for superficial sites like lymph nodes or liver lesions, particularly in resource-limited settings. Biopsy procedures provide definitive confirmation by sampling tissue for histopathological analysis to verify malignant cells and their origin. Core needle uses a larger needle to extract tissue cores, allowing assessment of architecture and to distinguish metastatic from primary tumors, ideal for solid organ lesions. (FNA) employs a thinner needle to aspirate cells, offering rapid cytological evaluation for accessible sites like nodes, though it may yield insufficient material for molecular testing in some cases. These minimally invasive methods minimize risks compared to surgical while enabling decisions based on genetic profiling. Laboratory tests support non-invasive detection and monitoring of metastasis through circulating biomarkers. Tumor markers such as (CEA) are elevated in colorectal metastases, aiding serial surveillance, while cancer antigen 125 (CA-125) signals ovarian or peritoneal spread. (ctDNA), detected via liquid from , identifies tumor-specific mutations for early metastatic detection and assessment, with higher sensitivity in advanced stages. Staging systems standardize the evaluation of metastatic involvement to predict behavior and inform management. The TNM classification, developed by the Union for International Cancer Control (UICC), categorizes metastasis via the M stage: M0 indicates no distant spread, while M1 denotes presence, further subdivided (e.g., M1a for single-site involvement) based on site and number of lesions. This system integrates with overall stage grouping (I-IV) to reflect disease burden, with stage IV encompassing metastatic disease across tumor types. Early detection faces challenges, particularly with micrometastases—submillimeter deposits below the resolution limits of standard imaging (typically 5-10 mm for CT/MRI). These occult lesions evade conventional modalities, contributing to recurrence, and necessitate advanced techniques like targeted for improved sensitivity.

The prognosis for patients with metastatic cancer, often classified as stage IV, varies significantly by the site, with median overall survival ranging from several months to several years. For instance, metastatic typically has a median survival of 3 to 6 months without treatment, though analyses as of 2023 report around 7 months overall for stage IV disease, with a 5-year relative of 3% for distant stage as of 2024. In contrast, metastatic cancer shows longer median survival, historically around 24 to 30 months, with estrogen receptor-positive cases extending to 32 months in the and improving to 57 months by 2010 due to evolving therapies; as of 2024, the 5-year relative for distant stage is 32%. Metastatic non-small cell lung cancer (NSCLC) carries a poor outlook in untreated or advanced cases, with median survival as short as 3 to 4 months for poor or untreated patients involving multiple sites, though standard treatments like plus yield median overall survival of 12 to 19 months as of 2025. These differences highlight the aggressive nature of certain primaries like and compared to more indolent ones like . Several prognostic indicators influence outcomes in metastatic disease, including the number of metastatic sites, patient , response to therapy, and tumor genetic markers. A greater number of metastatic sites is associated with increased risk of death in cohorts. , such as an Eastern Cooperative Oncology Group (ECOG) score of 1 or higher, independently predicts worse survival across various cancers, serving as one of the most powerful factors for early mortality in advanced soft tissue sarcomas. Genetic markers like HER2 overexpression in or hormone receptor status further stratify risk, with HER2-positive showing improved prognoses when targeted appropriately. Response to initial therapy also modulates survival, though it is assessed dynamically in clinical practice. The location of metastases profoundly impacts , with visceral involvement (e.g., liver or ) generally conferring a worse outlook than bone-only spread. In , patients with bone-only metastases have a survival of around 28 months, compared to 13 months for those with visceral metastases. Similar patterns hold across other primaries, where bone-only disease is linked to more stable progression and longer than visceral-dominant patterns, though the presence of extraskeletal visceral sites remains a dominant negative factor. Conceptual references to Kaplan-Meier survival curves in these studies illustrate steeper declines in visceral cases, emphasizing the prognostic weight of metastatic . Recent advancements in targeted therapies and have led to measurable improvements in for specific metastatic subsets, shifting median overall curves upward in Kaplan-Meier analyses. For example, HER2-targeted agents like and have enhanced outcomes in HER2-positive , contributing to broader declines in mortality from de novo metastatic disease. Matched targeted therapies in molecularly profiled tumors yield benefits and overall gains of up to 25% in response rates for advanced cases. These gains are most pronounced in cancers with actionable mutations, such as BRAF-targeted therapy in metastatic , where population-level has significantly improved since the mid-2010s; as of 2024, half of patients treated with combination inhibitors achieve 10-year cancer-free .

Pathophysiology

Multi-Step Process

Metastasis involves a complex, multi-step process known as the metastatic cascade, during which cancer cells detach from the , enter the circulation, survive transit, exit the vasculature, and establish secondary tumors at distant sites. This cascade begins with local , where tumor cells breach the and surrounding to infiltrate adjacent tissues. Following invasion, cells undergo intravasation, entering the bloodstream or lymphatic vessels to become circulating tumor cells (CTCs). In circulation, CTCs must evade immune detection and resist mechanisms to reach potential metastatic sites. Upon arrival, allows CTCs to exit the vessels and infiltrate target organs, initially forming micrometastases—small clusters of tumor cells that may remain dormant. Finally, these micrometastases can progress to macrometastases, forming clinically detectable tumors capable of further dissemination. A critical cellular process enabling the initial local invasion is the epithelial-mesenchymal transition (EMT), whereby epithelial tumor cells acquire mesenchymal traits to enhance motility and invasiveness. During EMT, cells lose cell-cell adhesion through downregulation of E-cadherin, a key component of adherens junctions, while upregulating mesenchymal markers such as and N-cadherin, facilitating degradation of the via proteases like matrix metalloproteinases. This transition is reversible, with a potential mesenchymal-to-epithelial transition (MET) occurring later to support colonization at secondary sites. EMT is orchestrated by transcription factors including , , and Twist, which suppress E-cadherin expression and promote migratory behavior.00702-0) Once in circulation as CTCs, the vast majority fail to form metastases due to the inherent inefficiency of the process, with fewer than 0.01% of CTCs successfully colonizing distant organs. This inefficiency arises primarily from challenges in surviving the harsh circulatory environment, including , immune surveillance, and anoikis—a form of triggered by detachment from the . To overcome anoikis, CTCs activate survival pathways such as integrin-mediated signaling or , clustering with platelets or neutrophils for protection, which enhances their viability during transit. Intravasation often occurs at leaky tumor-associated vessels, while involves CTC to endothelial cells via selectins and , followed by transmigration into the tissue parenchyma. The transition from micrometastases to macrometastases requires adaptation to the new microenvironment, including the induction of to ensure nutrient and oxygen supply for sustained growth. in metastatic lesions is driven by (VEGF) signaling, where tumor cells and stromal cells secrete VEGF-A to bind VEGF receptors on endothelial cells, promoting vessel sprouting and permeability. This neovascularization not only supports tumor expansion but also facilitates further intravasation, perpetuating the metastatic cycle. Without adequate , micrometastases often remain dormant, highlighting its rate-limiting role in metastatic progression.

Key Factors Involved

Genetic and epigenetic alterations play pivotal roles in driving the metastatic potential of cancer cells by enhancing invasion and survival capabilities. Mutations in key tumor suppressor genes such as TP53 often confer gain-of-function properties that promote epithelial-mesenchymal transition (EMT) and motility, facilitating the initial steps of dissemination. Similarly, oncogenic mutations in activate downstream signaling pathways that upregulate genes involved in invasion and cytoskeletal reorganization, thereby enabling tumor cells to breach tissue barriers. Loss-of-function mutations in PTEN, a negative regulator of the PI3K/AKT pathway, further amplify pro-invasive signals by increasing cell migration and resistance to anoikis. Epigenetic changes, including aberrant and modifications, complement these genetic hits by silencing metastasis suppressor genes like KISS1 or activating pro-metastatic loci through enhancer remodeling, thus sustaining an invasive phenotype across cell generations. The tumor microenvironment (TME) profoundly influences metastasis by providing a supportive ecosystem that nurtures cancer cell dissemination. Stromal cells, such as cancer-associated fibroblasts (CAFs), secrete growth factors like TGF-β that induce EMT and extracellular matrix (ECM) stiffening, creating tracks for tumor cell migration. ECM remodeling is critically mediated by matrix metalloproteinases (MMPs), enzymes overexpressed in the TME that degrade basement membranes and collagen, allowing invasive protrusions and collective cell movement. Immune evasion within the TME is facilitated by upregulated PD-L1 expression on tumor and stromal cells, which binds PD-1 on T cells to suppress cytotoxic responses and permit unchecked metastatic progression. Inflammation and hypoxia emerge as key initiators of metastasis by altering cellular signaling in the primary tumor site. Chronic inflammation recruits myeloid-derived suppressor cells and cytokines like IL-6, which foster an immunosuppressive milieu conducive to invasion. Hypoxic conditions, prevalent in rapidly growing tumors, stabilize hypoxia-inducible factor-1α (HIF-1α), a transcription factor that upregulates genes encoding VEGF for angiogenesis, LOX for ECM cross-linking, and Twist for EMT, thereby priming cells for metastatic escape. The HIF-1α pathway intersects with inflammation by enhancing NF-κB activity, amplifying pro-metastatic gene expression under low-oxygen stress. Circulating factors, particularly tumor-derived exosomes, act as messengers that precondition distant organs for metastasis by establishing a pre-metastatic niche. These extracellular vesicles encapsulate miRNAs, such as miR-25-3p, which are transferred to endothelial cells at secondary sites, downregulating proteins like ZO-1 and promoting for incoming cancer cells. Exosomal miRNAs also modulate immune cell recruitment and ECM deposition in the niche, creating a fertile ground for without direct tumor cell presence.

Routes of Spread

Cancer cells disseminate from primary tumors through several primary anatomical pathways, each facilitating metastasis to distant sites via distinct vascular, lymphatic, or tissue-specific routes. These pathways enable tumor cells to invade surrounding structures and establish secondary growths, with the choice of route influenced by the 's location and type. Hematogenous spread involves the direct entry of cancer cells into the bloodstream, typically through intravasation into venules or capillaries near the primary tumor. This route is prevalent in sarcomas, which frequently metastasize to the lungs due to the first-pass effect of filtering circulating tumor cells. Similarly, epithelial carcinomas, such as those originating in the colorectum, commonly spread to the liver via the , highlighting how anatomical drainage patterns dictate initial metastatic sites. Once in circulation, cells must survive shear forces and immune surveillance before extravasating into target organs. Lymphatic spread occurs when tumor cells invade lymphatic vessels and travel to regional lymph nodes, which act as sentinel sites for initial dissemination. This pathway is characteristic of carcinomas like and melanomas, where lymphatic drainage directs cells to axillary or inguinal nodes, respectively. Sentinel lymph node biopsy, a standard diagnostic tool, identifies early involvement in approximately 20% of breast cancer cases and informs and treatment decisions, such as axillary dissection. From lymph nodes, cells may further enter the and join systemic circulation for distant spread. Transcoelomic spread refers to the dissemination of cancer cells across body cavities, such as the or pleura, without relying on vascular routes. In , the predominant example, tumor cells detach from the primary site, form multicellular spheroids in , and implant on serosal surfaces like the omentum or diaphragm, driven by respiratory movements and . This process, facilitated by matrix metalloproteinases that degrade the for adhesion, often results in malignant accumulation due to factors, contributing to significant morbidity in advanced disease. Canalicular spread is a rare metastatic route involving the propagation of malignant cells along anatomical canalicular spaces, such as ducts or tubular structures. This pathway differs from vascular and has been documented in select carcinomas, including those of the , where cells may track along glandular ducts, and head and neck tumors involving salivary or biliary ducts. Though uncommon, it underscores the tumor's ability to exploit pre-existing anatomical conduits for local extension. Perineural invasion serves as a hybrid dissemination route, where cancer cells infiltrate and travel along sheaths, often combining elements of direct extension and neurotropism. Prevalent in head and neck malignancies, such as and , this spread affects 30-100% of cases depending on tumor type and involves like the trigeminal (V) and facial (VII). Tumor cells propagate antegrade from peripheral sites or retrograde toward the brainstem, entering perineural spaces and potentially the or Meckel's cave, which complicates surgical resection and worsens .

Organ-Specific Patterns

The concept of organ-specific patterns in metastasis, often referred to as organotropism, describes the non-random preference of cancer cells to disseminate and colonize particular distant sites, rather than spreading uniformly across all organs. This phenomenon was first articulated in the "seed and soil" hypothesis proposed by English surgeon Stephen Paget in 1889, based on autopsy observations of 735 cases, where he noted that secondary tumors formed preferentially in compatible host tissues, likening metastatic cancer cells (the "seeds") to plant seeds that only thrive in suitable microenvironments (the "soil"). Paget's theory challenged the prevailing view of metastasis as a passive, mechanical process and emphasized the active role of organ-specific factors in fostering tumor growth.49915-0/fulltext)70201-8/fulltext) Modern interpretations of the seed-and-soil hypothesis highlight molecular interactions between circulating tumor cells (CTCs) and target organ microenvironments, such as chemokine signaling axes that guide cell homing. A prominent example is the /SDF-1 (also known as ) axis in metastasis to , where tumor cells expressing the receptor are attracted to stromal cells secreting SDF-1, promoting adhesion, survival, and proliferation in this niche; this interaction is upregulated in approximately 70% of advanced cases that develop bone metastases. Similar tropisms occur in , where over 80% of advanced cases involve due to analogous chemokine-mediated homing and favorable osteoblastic responses. These patterns underscore how compatible biochemical cues, including growth factors and components, determine metastatic success. Clinically observed organ-specific frequencies further illustrate these preferences across cancer types. For instance, commonly metastasizes to (in about 65-75% of metastatic cases), (20-30%), and liver (20-25%), while preferentially targets the liver (up to 50% of cases) via portal venous drainage and supportive hepatic sinusoidal endothelium. and frequently seed the brain (10-20% for non-small cell lung cancer and 15-20% for melanoma), exploiting the blood-brain barrier's selective permeability for neural-like tumor cells. shows a strong toward (84% of metastatic sites in autopsy series), driven by endothelin-1 and signaling that mimic processes. These statistics, derived from large and clinical cohorts, reveal consistent patterns that inform and monitoring, with multi-organ involvement worsening outcomes. Emerging research refines the seed-and-soil framework by incorporating dynamic elements like and gradients that direct CTC extravasation and settlement. Increased endothelial permeability, often induced by tumor-secreted VEGF, facilitates CTC escape from circulation into target organs, particularly in and liver metastases where leaky vasculature enhances diapedesis. gradients, such as those formed by SDF-1 or CCL21, create directional cues that steer CTCs toward pre-metastatic niches prepared by primary tumor-derived exosomes, amplifying organ in models of and colorectal cancers. These mechanisms highlight the interplay between tumor cell intrinsic properties and host organ preparedness, offering insights into why certain sites resist colonization.

Relation to Primary Tumor

Molecular Differences

Metastatic cancer cells often arise through clonal from subpopulations within the , exhibiting increased intratumor heterogeneity and acquiring new that confer advantages for and . This involves macro-evolutionary leaps, such as chromosomal alterations, that drive the selection of aggressive clones capable of metastasis, with studies showing greater subclonal diversity in metastatic lesions compared to across various cancers. For instance, in , subclonal contributes to heightened heterogeneity, enabling adaptation to distant sites and resistance to therapy.30066-1) Epigenetic modifications further distinguish metastatic cells, with distinct DNA methylation patterns emerging between primary tumors and secondary sites. In colorectal cancer, metastasis-competent circulating tumor cells display unique methylation signatures, including widespread hypomethylation and hypermethylation at promoter regions of genes involved in Wnt signaling and , setting them apart from both primary and established metastatic cells. Similarly, in , epigenomic reprogramming, including altered , links metabolic shifts to metastatic progression, with primary tumor subclones showing differential global epigenetic states that seed distant metastases. Phenotypic shifts in metastatic cells include enhanced stem-like properties and metabolic reprogramming, amplifying the Warburg effect to support invasion and colonization. Metastatic cells upregulate glycolytic enzymes like , , and LDHA under hypoxia, leading to increased lactate production and suppressed , which contrasts with the metabolic profile of cells adapted to nutrient-rich environments. Cancer stem cells within metastases often exhibit heightened fatty acid oxidation for self-renewal and stemness maintenance, further differentiating them phenotypically. In , this reprogramming, including citrate accumulation driving expression, underscores the metastatic potential absent in primary lesions. Specific examples highlight these molecular divergences; in non-small cell lung cancer, EGFR amplification is more prevalent in metastatic lesions than in s, occurring in a significant subset of metastatic cases and correlating with aggressive progression.

Clinical Distinctions

Metastatic tumors often exhibit greater clinical aggressiveness compared to primary tumors, manifesting as accelerated growth and enhanced resistance to therapies. This increased aggressiveness stems from the selective pressures encountered during dissemination, resulting in metastases that are more challenging to control locally. For instance, while primary tumors may be amenable to surgical resection, metastatic lesions frequently necessitate systemic therapies such as or targeted agents due to their disseminated nature and propensity for rapid progression. Metastases also display heightened heterogeneity, both within individual lesions and across multiple sites, which contributes to variable responses to treatment; subclones resistant to specific drugs can predominate, leading to disease progression despite initial efficacy against the primary tumor.00260-7) A notable clinical distinction arises in growth rates and therapeutic sensitivities, particularly in hormone-dependent cancers. In , for example, metastatic sites may lose (ER) expression relative to the , with discordance rates reported at 10-20%, thereby rendering endocrine therapies ineffective and requiring a shift to alternative regimens. This loss, observed in up to 24% of cases transitioning from ER-positive primary to ER-negative metastases, correlates with poorer and underscores the need for re-biopsy to guide management. Such changes highlight how metastatic can alter tumor in ways that diminish responsiveness to hormone-targeted interventions originally effective against the primary lesion. The polyclonal origins of metastases foster substantial intra-tumor heterogeneity, complicating clinical and strategies. Derived from multiple cells within the , metastatic lesions harbor diverse subclonal populations that evolve independently, with only about 55% of somatic mutations detectable in a single sample. This heterogeneity can lead to discrepancies in prognostic assessments and treatment predictions, as regional variations in signatures may influence outcomes differently across sites. Consequently, clinicians must consider multi-site sampling or liquid biopsies to capture this diversity and avoid underestimating the tumor's adaptive potential. Clinical management further diverges based on metastatic burden, exemplified by oligometastatic versus polymetastatic . Oligometastatic states, involving 1-5 lesions, permit aggressive local interventions like or stereotactic body radiotherapy alongside , potentially improving by up to 38% compared to polymetastatic cases with widespread involvement. In contrast, polymetastatic disease typically relies on palliative systemic approaches due to extensive , yielding inferior overall survival ( 0.65 for oligometastatic advantage). These distinctions emphasize the prognostic and therapeutic implications of metastatic extent, guiding personalized strategies to optimize outcomes.

Management

Treatment Approaches

Treatment of metastatic cancer primarily relies on systemic therapies to address disseminated disease, with localized interventions reserved for specific symptomatic or limited sites. Systemic , such as taxanes (e.g., and ), remains a cornerstone for many metastatic solid tumors, including and cancers, by stabilizing to inhibit and induce . These agents are often used in combination regimens to enhance efficacy, particularly in cases where targeted options are unavailable. For patients with bone metastases, bone-modifying agents such as intravenous bisphosphonates (e.g., ) or subcutaneous are recommended every 3-4 weeks to prevent or delay skeletal-related events, including pathologic fractures, , and hypercalcemia, in accordance with guidelines from organizations like the European Society for Medical Oncology (ESMO) and the (NCCN). Targeted therapies exploit specific molecular alterations in metastatic cells; for instance, trastuzumab, a monoclonal antibody against HER2, is standard for HER2-positive metastatic breast cancer, binding to the receptor to block signaling and promote antibody-dependent cytotoxicity. In HER2-positive disease, it is typically combined with chemotherapy like taxanes or pertuzumab for improved response rates. Immunotherapy, particularly checkpoint inhibitors such as pembrolizumab, which targets PD-1 to unleash T-cell responses, is approved for metastatic cancers with high microsatellite instability or PD-L1 expression, including non-small cell lung cancer and melanoma. For hormone receptor-positive metastatic cancers, such as or , endocrine therapy inhibits or signaling to suppress tumor growth; examples include , aromatase inhibitors like , or . Endocrine resistance, often driven by ESR1 mutations or pathway crosstalk, develops in many patients, necessitating switches to alternative agents like or combination with CDK4/6 inhibitors. Localized treatments target isolated or symptomatic metastases. External beam radiation therapy is effective for painful bone metastases, delivering doses like 8 Gy in a single fraction or 30 Gy in 10 fractions to provide rapid palliation in 60-80% of cases. is considered for oligometastatic disease, defined as 1-5 sites, to resect resectable lesions in organs like the or liver, potentially improving control when combined with . Ablation techniques, such as , use heat to destroy small metastatic tumors in the liver or , offering a minimally invasive option for patients unfit for . Management of metastatic disease adopts a multidisciplinary approach, involving oncologists, surgeons, radiation oncologists, and supportive care specialists to tailor sequencing and combinations per evidence-based guidelines like those from the (NCCN). Treatment selection is guided by diagnostic confirmation of metastatic sites and tumor , ensuring alignment with performance status and goals.

Challenges and Complications

One of the primary barriers to effective treatment of metastatic cancer is drug resistance, which arises through mechanisms such as the overexpression of ATP-binding cassette (ABC) transporters that function as efflux pumps, actively expelling chemotherapeutic agents from cancer cells and thereby reducing intracellular drug concentrations. Prominent examples include ABCB1 (P-glycoprotein), ABCG2, and ABCC1, which contribute to multidrug resistance (MDR) in various metastatic tumors, including those of the breast, lung, and colon, by mediating the transport of a wide range of substrates across cell membranes. Tumor heterogeneity further exacerbates this resistance, as metastatic lesions often exhibit genetic, epigenetic, and phenotypic diversity within the same patient, allowing subpopulations of resistant cells to survive and proliferate under therapeutic pressure. This intratumoral and intertumoral variability not only promotes adaptive evolution but also leads to incomplete responses to standard treatments like chemotherapy and targeted therapies. Treatment-induced toxicities pose significant complications, impairing patients' and sometimes necessitating dose reductions or treatment discontinuation. , a cornerstone for managing metastatic disease, frequently causes , characterized by sensory symptoms such as numbness, tingling, and pain, affecting 30-40% of patients receiving neurotoxic agents like taxanes or platinums. , used for palliation in metastatic sites such as the lungs or bones, can induce , an inflammatory response leading to cough, dyspnea, and , with incidence rates of 10-30% in thoracic irradiation cases due to direct cytotoxic effects and . Disease-related complications, including pathologic fractures from bone metastases, add further challenges; these fractures occur in 8-30% of patients with skeletal involvement, often from cancers like or , resulting from weakened bone structure and increased fracture risk under minimal trauma. Logistical challenges compound these clinical hurdles, particularly in metastatic cancer where care is often prolonged and multifaceted. Access to specialized care remains limited for many patients, with barriers including transportation difficulties, low , and geographic disparities, leading to delayed diagnoses or incomplete treatment courses. High costs of , estimated at $222 billion annually in the U.S. for cancer care in 2025, with metastatic cases often incurring over $100,000 per patient in direct treatment expenses in the initial phase, impose substantial financial , often resulting in out-of-pocket burdens that affect adherence and outcomes. Ethical issues in advanced disease, such as balancing aggressive interventions against quality-of-life preservation and navigating patient autonomy in end-stage scenarios, require individualized amid uncertainties in and treatment benefits. Specific to metastasis, sanctuary sites like the present unique delivery obstacles due to the blood- barrier (BBB), a protective endothelial layer that restricts penetration and limits the efficacy of systemically administered agents in treating metastases from primaries such as or . This barrier maintains lower exposure in metastatic lesions compared to extracranial sites, contributing to poorer responses and highlighting the need for strategies that overcome these physiological constraints without broadly referencing emerging solutions.

Research and Advances

Current Investigations

Ongoing clinical trials are evaluating the utility of liquid biopsies in monitoring circulating tumor cells (CTCs) and (MRD) to detect metastatic recurrence post-treatment. The DARE phase II trial (NCT04567420) in early-stage assesses ctDNA-based MRD to guide decisions, reporting a 3.3% ctDNA positivity rate across 1,120 assays and aiming to reduce recurrence through targeted interventions. Similarly, the ZEST trial in early-stage evaluates ctDNA MRD after , which closed early with a 7.7% positivity rate, suggesting benefits from earlier post-treatment screening for metastasis risk. In , the ongoing NCT05704530 trial (through 2026) uses ctDNA to detect MRD post-resection. For , NCT04966663 investigates ctDNA in post-surgical monitoring, while a 2024 study using rare cell sorters detected CTCs in patients post-treatment, linking higher counts to metastasis progression. These trials highlight liquid biopsies' non-invasive role in real-time metastasis surveillance, with technologies like CAPP-Seq achieving 95% specificity for low-level ctDNA detection in NSCLC MRD. Studies on metastasis suppressors, such as the NM23 (NME1) gene, continue to explore their mechanistic roles in inhibiting tumor dissemination. A 2023 perspective emphasizes NM23's involvement in dynamin-mediated membrane remodeling and mitochondrial dynamics, distinguishing its suppression of metastasis from growth without affecting proliferation. Recent research identifies NME1's role in tumor progression, including in gastric cancer where FBXO32 downregulates NME1 to promote progression. Additionally, 2024 investigations show elevated extracellular vesicular NM23-H1 subdues pro-metastatic signaling in models, reinforcing its suppressor function at early dissemination stages. Parallel advancements in imaging include PSMA-PET for metastasis detection, with the proPSMA (2020) reporting 92% accuracy for nodal/distant lesions versus 65% for conventional methods, and 98% specificity for bone metastases. A 2024 using PSMA-PET/CT-guided radiotherapy in oligometastatic castration-resistant achieved a 16.4-month progression-free survival. Furthermore, data from high-risk patients staged with 68Ga-PSMA-PET/CT showed improved outcomes, altering treatment plans in approximately 28% of cases. Epidemiological research post-2020 documents rising metastasis incidence by primary cancer type, attributed to improved survival from localized disease. Using SEER data (1988–2018) projected to 2040, incidence shows an annual percent change (APC) of 1.84, 1.66, 0.40, and 2.53, leading to an overall rate of 34 per 100,000 by 2040. This trend reflects a 46.7% increase in long-term survivorship odds for metastatic patients, driven by advances in management. In specifically, metastatic incidence rose from 5.8 to 7.9 per 100,000 women between 2001 and 2021, with a 2025 analysis confirming inverse relationships between metastatic burden and overall survival across subtypes. Collaborative efforts like the METABRIC dataset facilitate genomic profiling of metastases, integrating copy number and expression data from nearly 2,000 primary tumors. A 2024 study using METABRIC analyzed coexpression of MET and ESR genes, identifying patterns linked to metastatic potential in 2,509 patients. This resource supports ongoing observational studies in metastasis , enabling validation of suppressor genes and molecular subtypes without relying on fresh metastatic samples.

Emerging Therapies

Emerging therapies for metastasis focus on disrupting key molecular drivers and microenvironmental cues that facilitate tumor dissemination and colonization. Targeted therapies against specific metastatic drivers have shown promise in preclinical and early-phase clinical settings. For instance, such as and exploit in BRCA-mutated metastatic cancers, particularly and ovarian, by impairing in homologous recombination-deficient cells. In phase III trials like OlympiA (NCT02032823, 2021), reduced invasive disease-free survival events by 42% in BRCA1/2-mutated high-risk early , with benefits extending to metastatic settings in ongoing studies. Bispecific antibodies, which simultaneously engage tumor antigens and immune effectors, represent another advance; , targeting EGFR and MET, achieved an objective response rate of 40% in phase II trials for EGFR exon 20 insertion-mutated metastatic non-small cell (NSCLC), improving to 11.4 months in phase III (PAPILLON, 2023). Immunotherapies tailored for metastatic solid tumors are evolving to overcome immunosuppressive barriers in distant sites. Chimeric antigen receptor (CAR) T-cell therapies, adapted for solid tumors, target metastasis-associated antigens like claudin18.2 in gastrointestinal cancers; in a phase I (NCT03874897, 2020-2024), claudin18.2 -T cells yielded a 48.6% objective response rate and 73% disease control rate in advanced metastatic patients, with durable responses in some cases despite challenges. Cancer vaccines targeting , such as neoantigens, aim to elicit systemic anti-metastatic immunity; personalized neoantigen vaccines in phase I/II for metastatic (2023-2025) induced T-cell responses against metastatic lesions, delaying progression in 50% of patients when combined with checkpoint inhibitors. These approaches highlight the shift toward multi-antigen strategies to address metastatic heterogeneity. Anti-metastatic agents directly interfere with epithelial-mesenchymal transition (EMT) and pre-metastatic niche formation to prevent dissemination. TGF-β inhibitors, such as galunisertib, block EMT induction in metastatic cells; in a phase Ib trial (2021) for metastatic , galunisertib combined with demonstrated tolerability and partial responses by reducing TGF-β-driven invasion markers. LOXL2 blockers target remodeling in the pre-metastatic niche; the small-molecule inhibitor PXS-S1C reduced LOXL2 expression and inhibited metastasis in preclinical mouse models (2022), while a bi-thiazole LOXL2 inhibitor rewired architecture to enhance response in metastases (2024), achieving 60% tumor reduction in lung metastasis models. These agents offer preventive potential by disrupting early metastatic priming. Recent advances from 2020-2025 integrate nanotechnology and artificial intelligence to enhance therapeutic precision against metastasis. Nanoparticle-based drug delivery systems enable site-specific targeting of metastatic lesions; lipid nanoparticles encapsulating doxorubicin showed potent anti-metastatic effects in pulmonary melanoma models (2023), reducing lung metastases by 70% through enhanced vascular extravasation and pH-responsive release. AI-driven models predict metastatic risk by analyzing multi-omics data; a deep learning framework (2024) using radiomics from CT scans predicted breast cancer metastasis with 85% accuracy, outperforming traditional nomograms and guiding early intervention in high-risk patients. As of 2025, ongoing investigations include AI-enhanced ctDNA analysis for personalized metastatic risk assessment. These innovations underscore a convergence of delivery platforms and predictive tools to optimize anti-metastatic outcomes.

History and Terminology

Historical Development

The understanding of metastasis began in the early with initial observations of cancer spread beyond the . In 1829, French physician Claude Recamier coined the term "metastasis" in his book Recherches sur le traitement du cancer, describing the process as the displacement of morbid matter from one site to another, marking the first systematic recognition of secondary tumor formation in distant organs. This concept built on earlier anecdotal reports but formalized the idea that cancers could disseminate systematically rather than merely through local extension. By the 1860s, advanced this view with his embolism theory, proposing in Die Cellularpathologie (1858) and subsequent works that tumor cells detach from the primary site, enter the bloodstream or lymphatics as emboli, and lodge in remote tissues to form secondary growths, emphasizing cellular dissemination over humoral factors. Key theoretical milestones emerged in the late 19th and early 20th centuries, shifting focus toward organ-specific patterns and mechanics of spread. In 1889, British surgeon Stephen Paget introduced the "seed-and-soil" hypothesis in his seminal paper "The distribution of secondary growths in cancer of the breast," published in The Lancet, arguing that metastatic cells (the "seeds") preferentially grow in compatible host organs (the "soil") based on autopsy data from 735 breast cancer cases, challenging purely random embolization. This idea gained traction despite counterarguments; for instance, in 1894, American surgeon William Halsted highlighted the critical role of lymphatics in breast cancer dissemination through his analysis of surgical outcomes at Johns Hopkins, advocating radical mastectomy to interrupt orderly lymphatic progression from primary tumor to regional nodes. The 1920s saw James Ewing counter Paget's affinity model with his mechanical theory, outlined in the 1928 edition of Neoplastic Diseases, positing that metastatic patterns arise primarily from hemodynamic factors—such as blood flow direction and capillary trapping—rather than inherent compatibility between tumor cells and target sites. Mid-20th-century advances integrated experimental and therapeutic insights, laying groundwork for systemic approaches. The 1950s marked the advent of the first trials targeting metastatic disease, spurred by wartime discoveries of nitrogen mustards; notably, in 1956, researchers Roy Hertz and Min Chiu Li achieved remissions in using , demonstrating chemotherapy's potential to address disseminated cancer beyond surgical resection. The epithelial-mesenchymal transition (EMT) was identified in the 1980s as a key cellular mechanism enabling metastatic invasion, first linked to cancer by studies showing how epithelial tumor cells acquire migratory mesenchymal traits to breach basement membranes and enter circulation. The genomic era, ignited by the Human Genome Project's completion in 2003, revolutionized metastasis research by enabling high-throughput sequencing to dissect molecular underpinnings. This facilitated studies on clonal evolution in the , revealing how metastatic lesions arise from subsets of cells that accumulate mutations during dissemination and adaptation, as evidenced by multi-region sequencing of colorectal and cancers showing branching phylogenies and at distant sites. In the , further progress included the development of metarrestin, an experimental drug targeting a protein essential for metastatic cell survival, showing promise in preclinical models of as of 2023, and expanded use of single-cell sequencing to uncover dynamic clonal heterogeneity in metastasis. These insights underscored metastasis as a Darwinian process, informing precision strategies.

Etymology

The term "metastasis" derives from the words meta (μετά), meaning "beyond" or "after," and stasis (στάσις), meaning "standing" or "placement," literally translating to "displacement" or "removal from one place to another." In ancient medicine, (c. 460–370 BCE) first applied the term to describe the migration of bodily fluids, such as , from one site to another, as documented in works like , where it denoted a shift in pathological processes rather than specifically cancerous spread. By the , the term gained prominence in through the work of French physician Joseph-Claude-Anthelme Récamier, who in introduced "métastase" to characterize the dissemination of cancer from a to distant sites, replacing earlier descriptive phrases like "secondary growths" or "remote deposits." Récamier's observations during autopsies highlighted the process as a migration of malignant cells via or , standardizing the terminology in and shifting its focus from general disease progression to cancer-specific propagation. Related terms emerged in the late to describe specific metastatic patterns. "Micrometastasis" was coined in 1971 by pathologists Andrew G. Huvos and colleagues to refer to subclinical clusters of cancer cells (typically 0.2–2 mm in size) undetectable by routine , emphasizing early, microscopic dissemination. Similarly, "oligometastasis" was introduced in 1995 by Hellman and Ralph R. Weichselbaum to denote a limited number of metastatic sites (often fewer than five), suggesting an intermediate state between localized and widespread disease amenable to targeted therapies. Over time, usage of "metastasis" has evolved culturally from a neutral descriptor of pathological displacement in ancient texts to a modern indicator of advanced , inherently implying poor and therapeutic resistance due to its association with systemic cancer progression.

References

  1. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/metastasis
  2. https://www.cancer.gov/about-nci/organization/dcb/news/systemic-effects-of-cancer-think-tank-presentation-agendas
  3. https://www.cancer.gov/types/metastatic-cancer
  4. https://www.cancer.gov/news-events/cancer-currents-blog/2025/metastasis-dormant-cancer-cells-immune-system
  5. https://www.cancer.org/cancer/understanding-cancer/what-is-cancer/advanced-and-metastatic-cancer.html
  6. https://my.clevelandclinic.org/health/diseases/22213-metastasis-metastatic-cancer
  7. https://www.ncbi.nlm.nih.gov/books/NBK507890/
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC4951968/
  9. https://www.cancer.org/cancer/diagnosis-staging/tests/imaging-tests/imaging-radiology-tests-for-cancer.html
  10. https://www.cancer.gov/about-cancer/diagnosis-staging/staging
  11. https://www.cancercouncil.com.au/news/10-common-tests-and-scans-used-to-diagnose-cancer/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC5527766/
  13. https://dctd.cancer.gov/research/research-areas/imaging/basics
  14. https://www.mayoclinic.org/tests-procedures/needle-biopsy/about/pac-20394749
  15. https://www.cancer.org/cancer/diagnosis-staging/tests/biopsy-and-cytology-tests/biopsy-types.html
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC5769667/
  17. https://pubs.rsna.org/doi/abs/10.1148/rg.2021210005
  18. https://www.mdpi.com/1422-0067/24/17/13219
  19. https://www.uicc.org/what-we-do/sharing-knowledge/tnm
  20. https://jnm.snmjournals.org/content/61/7/1079
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC9340332/
  22. https://pubmed.ncbi.nlm.nih.gov/36353987/
  23. https://www.cancer.org/cancer/types/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html
  24. https://pubmed.ncbi.nlm.nih.gov/30627694/
  25. https://seer.cancer.gov/statfacts/html/breast.html
  26. https://www.medicalnewstoday.com/articles/life-expectancy-and-survival-rates-for-metastatic-lung-cancer
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC11937135/
  28. https://www.sciencedirect.com/science/article/abs/pii/S1877782114000976
  29. https://www.dana-farber.org/newsroom/news-releases/2024/long-term-metastatic-melanoma-survival-dramatically-improves-on-immunotherapy
  30. https://www.nature.com/articles/s41392-020-0134-x
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC8345184/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC5242415/
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC1853000/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC3296207/
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC4670555/
  36. https://www.pnas.org/doi/10.1073/pnas.0908428107
  37. https://aacrjournals.org/cancerdiscovery/article/11/8/2094/666213/Oncogenic-KRAS-Recruits-an-Expansive
  38. https://www.sciencedirect.com/science/article/pii/S0304419X23002093
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC8524384/
  40. https://www.nature.com/articles/s41419-023-06110-6
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC10007858/
  42. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-018-0928-4
  43. https://pmc.ncbi.nlm.nih.gov/articles/PMC4573780/
  44. https://www.liebertpub.com/doi/10.1089/ars.2019.7935
  45. https://www.nature.com/articles/s41467-018-07810-w
  46. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-024-02081-0
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC11374872/
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC4593771/
  49. https://pmc.ncbi.nlm.nih.gov/articles/PMC6545317/
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC4846400/
  51. https://pmc.ncbi.nlm.nih.gov/articles/PMC3555200/
  52. https://pubmed.ncbi.nlm.nih.gov/20166978/
  53. https://meridian.allenpress.com/aplm/article/132/6/931/460506/Metastatic-Patterns-of-Cancers-Results-From-a
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC4673677/
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC8353911/
  56. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-017-0742-4
  57. https://www.nature.com/articles/s41523-021-00363-0
  58. https://www.nature.com/articles/s41598-023-42037-w
  59. https://www.nature.com/articles/nrc.2017.11
  60. https://www.nature.com/articles/s41388-020-01432-7
  61. https://www.nature.com/articles/bjc2016152
  62. https://pubmed.ncbi.nlm.nih.gov/35466584/
  63. https://link.springer.com/article/10.1007/s10585-021-10144-5
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC7764472/
  65. https://doi.org/10.1200/JCO.1996.14.9.2584
  66. https://www.nejm.org/doi/full/10.1056/NEJMoa1113205
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC9106994/
  68. https://www.cancer.gov/news-events/cancer-currents-blog/2020/oligometastatic-cancer-directly-treating-cancer-metastases
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC9592970/
  70. https://pmc.ncbi.nlm.nih.gov/articles/PMC11135142/
  71. https://www.annalsofoncology.org/article/S0923-7534(20)39995-6/fulltext
  72. https://www.nccn.org/patients/guidelines/content/PDF/stage_iv_breast-patient.pdf
  73. https://jnccn.org/view/journals/jnccn/22/5/article-p331.xml
  74. https://www.cancer.gov/about-cancer/treatment/drugs/pembrolizumab
  75. https://www.ncbi.nlm.nih.gov/books/NBK546616/
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC11560879/
  77. https://www.nature.com/articles/s41523-023-00523-4
  78. https://www.astro.org/provider-resources/guidelines/astro-s-guideline-on-palliative-radiation-therapy-for-bone-metastases
  79. https://www.jtcvs.org/article/S0022-5223%2823%2900874-7/fulltext
  80. https://www.mayoclinic.org/tests-procedures/radiofrequency-ablation/about/pac-20385270
  81. https://pmc.ncbi.nlm.nih.gov/articles/PMC2408956/
  82. https://www.nccn.org/guidelines/guidelines-process/about-nccn-clinical-practice-guidelines
  83. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.648407/full
  84. https://pmc.ncbi.nlm.nih.gov/articles/PMC9066118/
  85. https://pmc.ncbi.nlm.nih.gov/articles/PMC10132823/
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC5656281/
  87. https://pmc.ncbi.nlm.nih.gov/articles/PMC7788688/
  88. https://www.ncbi.nlm.nih.gov/books/NBK559077/
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC12482500/
  90. https://newsroom.cigna.com/15-stats-illustrating-cancers-impact-on-people-employers-and-health-care-costs
  91. https://pmc.ncbi.nlm.nih.gov/articles/PMC4822976/
  92. https://www.cancernetwork.com/view/common-theme-among-ethical-issues-oncology-need-individualize-advanced-cancer-care
  93. https://aacrjournals.org/mct/article/18/11/2171/92558/Improved-Drug-Delivery-to-Brain-Metastases-by
  94. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.722917/full
  95. https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.1010
  96. https://clinicaltrials.gov/study/NCT05704530
  97. https://www.nature.com/articles/s41392-024-02021-w
  98. https://www.nature.com/articles/s41698-025-00984-9
  99. https://link.springer.com/article/10.1007/s10555-023-10130-1
  100. https://tcr.amegroups.org/article/view/102055/html
  101. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30297-6/fulltext
  102. https://doi.org/10.2967/jnumed.124.267922
  103. https://pmc.ncbi.nlm.nih.gov/articles/PMC12227496/
  104. https://pmc.ncbi.nlm.nih.gov/articles/PMC10224927/
  105. https://www.cdc.gov/united-states-cancer-statistics/publications/metastatic-breast-cancer.html
  106. https://www.nature.com/articles/s41598-025-12883-x
  107. https://ega-archive.org/studies/EGAS00000000083
  108. https://onlinelibrary.wiley.com/doi/10.1155/2024/2582341
  109. https://www.synapse.org/Synapse:syn1688369/wiki/54543
  110. https://www.nejm.org/doi/full/10.1056/NEJMoa2105215
  111. https://www.nature.com/articles/s41392-025-02269-w
  112. https://www.cancer.gov/news-events/cancer-currents-blog/2025/neoantigen-vaccine-pancreatic-kidney-cancer
  113. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1489701/full
  114. https://www.mdpi.com/1422-0067/23/20/12270
  115. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02450-3
  116. https://pmc.ncbi.nlm.nih.gov/articles/PMC4037932/
  117. https://link.springer.com/article/10.1023/A:1010606623499
  118. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)70201-8/fulltext
  119. https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.27509
  120. https://academic.oup.com/edrv/article/28/3/297/2354976
  121. https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%281965%2918:3%3C625::AID-CNCR2820180305%3E3.0.CO;2-Y
  122. https://www.sciencedirect.com/science/article/pii/S0092867404007020
  123. https://pmc.ncbi.nlm.nih.gov/articles/PMC3698498/
  124. https://www.science.org/doi/10.1126/sciadv.aay9691
  125. https://www.cancer.gov/news-events/cancer-currents-blog/2023/metarrestin-pancreatic-cancer-metastasis
  126. https://www.etymonline.com/word/metastasis
  127. https://pmc.ncbi.nlm.nih.gov/articles/PMC11591967/
  128. https://jbuon.com/archive/16-3-572.pdf
  129. https://www.sciencedirect.com/science/article/abs/pii/S0093775404001162
  130. https://pubmed.ncbi.nlm.nih.gov/32279519/
  131. https://pmc.ncbi.nlm.nih.gov/articles/PMC5703396/
Add your contribution
Related Hubs
Contribute something
User Avatar
No comments yet.