Molecular BIology of Cancer Topics
Once a malignant tumor has access to the vasculature, it is able to metastasize to other tissues. The process of metastasis starts with the invasion of venules, capilaries and lymphatics by malignant cels, a process known as intravasation (i.e. invasion of the vasculature). In order for detachement of cells from the original tumor and intravasation to occur, the tumor cells need to have decreased levels of cell adhesion molecules (CAMs), increased levels of proteases, and increased levels of motility factors.
The tumorigenic cells can travel with the blood to distant tisues. In order for thetumor cells to migrate from the blood into new tissue (extravasation) they must first agregate (arrest) in a capillary bed, forming an embolism, i.e. a multicell agregate that includes lymphocytes and platelets. Once the cells have attached to the capillary walls, they are able to migrate between endothelial cells. Cancer cells that have achieved intravasation may still die (90-99%) before reaching another tisue, due to mechanical stress in capillary beds, poor nutrition or immune surveillance.
The process of extravasation progresses from attachement to the capillary endothelial cells of a tissue, to retraction of endothelial cells and/or attachement to the denuded basement membrane, to enzyme digestion of and movement through the basement membrane, and finally entrance to the interstitial space.
Both hemodynamics and the microenvironment of a tissue contribute to organ-specific metastasis. Not all cancer cells will survive in al the tissues they trabvel to because different cancer cells require different combinations of growth factors, for example a GI carcinoma may metastasize to the liver but not to bone.
The vascular drainage for tumors of the GI track is mostly via the portal circulation, while tumors at other sites drain via the systemic veins. Therefore, the vascular spread of tumor cells reslts in mostly the cells being delivered initially to the lung or liver, where they are likely to be arrested in the capillary bed. If the tumor cells traverse the capillary bed of the first pass organ, they can distribute to other organs were they can be similarly trapped.
The experimental metastasis assay involves injecting athymic mice with tumor cells, intravenously After several days, organs are removed and tumor nodules are counted. The spontaneous metastasis assay requires implantation of tumor tissue subcutaneously or intramuscularly instead of IV, thus requires intravasation and extravasation for metastasis to occur. The experimental assay requires only extravasation.
Orthotopically (in the same tissue type) implanted tumors metastasize more readily than tumors implanted in ectopic (different) sites. For example, Egami et. al (1991) showed tat after injecting pancreaticx cancer cells into the pancreas of mice, 100% of mice develeped pancreatic tumors, 22% develepode liver tumors and 11% lymph node tumors. But if the pancreatic cancer cells were implanted subcutaneouisly there was no metastasis to other organs, even as 100% of mice developed pancreatic cancer.
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