metastasis metastasis metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. the newly pathological sites, then, are metastases (mets). it is generally distinguished from cancer invasion, which is the direct extension and penetration by cancer cells into neighboring tissues. metastasisother namesmetastatic diseaseillustration showing hematogenous metastasispronunciationmetastasis /mᵻˈtastəsɪs/ metastases /mə ˈtæs tə siːz/ specialtyoncology 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 acquire the ability to penetrate the walls of lymphatic or blood vessels, after which they are able to circulate through the bloodstream to other sites and tissues in the body. this process is known (respectively) as lymphatic or hematogenous spread. after the tumor cells come to rest at another site, they re-penetrate the vessel or walls and continue to multiply, eventually forming another clinically detectable tumor. this new tumor is known as a metastatic (or secondary) tumor. metastasis is one of the hallmarks of cancer, distinguishing it from benign tumors. most cancers can metastasize, although in varying degrees. basal cell carcinoma for example rarely metastasizes. 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. 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 cut surface of a liver showing multiple paler metastatic nodules originating from pancreatic cancer initially, nearby lymph nodes are struck early. the lungs, liver, brain, and bones are the most common metastasis locations from solid tumors. in lymph node metastasis, a common symptom is lymphadenopathy lung metastasis: cough, hemoptysis and dyspnea (shortness of breath) liver metastasis: hepatomegaly (enlarged liver), nausea and jaundice bone metastasis: bone pain, fracture of affected bones brain metastasis: neurological symptoms such as headaches, seizures, and vertigo although advanced cancer may cause pain, it is often not the first symptom. some patients, however, do not show any symptoms. when the organ gets a metastatic disease it begins to shrink until its lymph nodes burst, or undergo lysis. pathophysiology 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. 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 (1), the cancer stem cell hypothesis (2), and the macrophage–cancer cell fusion hybrid hypothesis (3). 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). factors involved 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. 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 and transforming growth factor beta. 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. 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. 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. besides forces, the regulation of various types of cell-cell and cell-matrix adhesions is crucial during metastasis. 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, is a crucial hallmark of cancer. it has therefore been suggested that angiogenesis inhibitors would prevent the growth of metastases. endothelial progenitor cells have been shown to have a strong influence on metastasis and angiogenesis. 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. the immune system is typically deregulated in cancer and affects many stages of tumor progression, including metastasis. 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. these epigenetic modifications in metastases may allow the proliferation and survival of disseminated tumor cells in distant organs. 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. 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. routes metastasis occurs by the following four routes: transcoelomic 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. lymphatic spread 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. 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. lymph node with almost complete replacement by metastatic melanoma. the brown pigment is focal deposition of melanin hematogenous spread 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. canalicular spread 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). organ-specific targets main sites of metastases for some common cancer types. primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases". 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. 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. 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. 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. 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. 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. 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. metastasis and primary cancer 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). it is estimated that 3% of all cancers are of unknown primary origin. studies have shown that, if simple questioning does not reveal the