B1

Adaptation ¬°it metastasis site

There is some debate, whether some cancers have simply accumulated many mutations during their development or whether all exhibit genomic instability leading to an increased rate of chromosome alterations, point mutations, and/or epigenetic defects (^2.5). This is not an academic question, because cancers with genomic instability will display greater variation and a higher risk of developing resistance. It seems indeed possible that true genomic instability develops in some cancers during progression, e.g. in CML (^10.4). Genomic instability in cancer cells can be derived from several sources, e.g. from defects in DNA repair and in mechanisms checking genomic integrity (^3.4).

Immortalization: Many cancer cells are 'immortalized', which means they are capable of a theoretically infinite number of cell divisions. Most human cells can undergo only a finite number of divisions, likely up to 60-80, before they irreversibly lose their ability to proliferate (^7.4). Obviously, the cells constituting the germ line are exempt from this restriction and so are tissue stem cells. For instance, hematopoetic stem cells in the bone marrow can be successively transplanted across several recipients and still remain capable of reconstituting the entire hematopoetic system, blood and immune cells. Immortality in stem cells is maintained by specific mechanisms such as expression of telomerase (^7.4), which is also found in cancers. Moreover, some human cancer cells can be maintained in tissue culture or as transplants in animals, designated 'xenografts', over many generations, as far as we can tell, infinitely many. On a note of caution, it is not certain that all human cancers are immortalized, since many cannot be grown in tissue culture or as xenografts. Even telomerase expression is not universal. To become life-threatening, however, a cancer does not need to consist of cells with infinite growth potential. Starting out from a single cell, 50 replications would yield up to 249 tumor cells, which must be compared to something between 1013 and 1014 normal cells in a human. Lethal cancers are much smaller than that.

Invasion and metastasis: A property more directly evident in human cancers is their ability for invasion and metastasis. Invasion and metastasis (^9) are the definitive criteria which distinguish benign from malignant tumors (the expression 'malignant tumor' is synonymous with cancer, Table 1.4). Moreover, invasion and metastasis, with tumor cachexia and immune suppression, account for most of the lethality of human cancers.

During invasion, cancers spread from their site of origin into different layers and parts of the same tissue, eventually growing beyond it and into neighboring structures. Invasion involves multiple steps and often substantial rebuilding of the tissue structure by the tumor cells, by other cells in the tissue responding to signals from the tumor cells, and by immune and inflammatory cells. Typically, in carcinomas, the basement membrane separating epithelium and mesenchyme is destroyed and tumor extensions push through the connective tissue and muscle layers. From some cancers, cells separate and migrate through the neighboring tissues, as single cells, in an Indian file pattern or as small, adherent cell clusters. Invasion is often accompanied by inflammation, so lymphocytes, granulocytes and macrophages are present in the invaded tissue and in the tumor mass.

An important component of malignant growth is neoangiogenesis (^9.4). The nutrient and oxygen supply from preexisting blood vessels is usually not sufficient to support growth of tumors beyond a size of a few mm. Therefore, cancers, but also some benign tumors, induce neoangiogenesis, which comprises the growth of new capillaries, and the rebuilding of existing blood vessels (^9.4). Lymph vessels can also be remodeled or newly formed.

During metastasis, cancer cells separate from the primary tumor and migrate by the blood or lymph to different organs where they form new tumors. Depending on the route, 'hematogenic' metastasis, which usually leads to metastases at distant organ sites, is distinguished from 'lymphogenic' metastasis, which leads initially to the formation of metastases in lymph nodes draining the region from which the cancer emerges. Like invasion, metastasis is really a multistep process. Thus, many more cancer cells enter the blood or lymph than actually form metastases. Important barriers are posed by the necessity to leave the blood stream at capillaries which carcinoma cells cannot pass ('extravasation') and to survive and resume proliferation in the microenvironment of a different tissue. In fact, individual cancer cells or small groups may end up in a different tissue only to survive over long periods without net growth. These 'micrometastases' are not detectable by current imaging techniquew, although they may be biochemically detectable by proteins secreted by the cancer cells. Over time, they may adapt to their new environment and expand to larger metastases that threaten the patient's life. This may occur several years after the primary tumor has been removed. Cancers differ in the extent and the sites to which they metastasize (^9). Generally, preferred organs for metastasis are those with extended microcapillary systems such as liver, lung, and bone.

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