Metastasis

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; 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. 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. 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. 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. 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

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.

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, 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). 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. In addition to genetic and biochemical regulation, mechanical forces and the physical properties of cancer cells and their surrounding microenvironment play an important role across multiple stages of metastasis, including invasion, intravasation, circulation, extravasation, and colonisation.

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