In clinical oncology, the term “invasive growth” refers to the ability of some cancer cells to leave their site of origin, to traverse anatomic barriers to cell movement — the basement membrane in the case of epithelial cancers — and to move to locations distant from the site of origin. Invasive growth is further classified as local or systemic, referring to the ability of some cancer cells to grow in locations adjacent to the site of origin or in locations distant from the site of origin. For most clinical classifications of stage of cancer, the presence of local or systemic tumor deposits (metastases) makes a major difference in the cancer stage.
Given the well-known and profound effects of HGF-Met signaling on cells’ morphology and invasive character, it is interesting to consider the biological characteristics of cells in patients with inherited mutations in the Met tyrosine kinase domain. Such germline mutations are clearly compatible with normal growth and development. Cancer in patients who carry such kinase-activated MET alleles typically occurs late in life and is confined to a single organ, the kidney. In genetic terms, the penetrance (the proportion of individuals with germline mutations in the MET gene who exhibit detectable renal tumors) is 40% by age 50. These renal cancers are indolent, slow-growing neoplasms. Even in the condition known as hereditary papillary renal carcinoma (one form of which is associated with MET mutations), the multiple, independently developing tumors display the clinical properties of invasive growth only late in the course of the disease. For this reason, urologic surgeons managing patients with this disorder generally wait until the largest renal tumor is 3 cm in diameter before operating.
These papillary renal cancers display a number of consistent somatic genetic changes, including duplication of the chromosome bearing the mutated MET gene and trisomy of chromosome 17. Hence, the development of papillary renal cancer likely requires a number of additional genetic changes along with the inherited MET mutation. Conversely, other human cancers, found in individuals with neither somatic nor germline mutations in MET, often show increased expression of Met protein. It is currently thought that this increased expression of Met contributes to invasive growth, but it must be acknowledged that these cells carry multiple genetic and epigenetic changes, making it difficult to isolate the contribution of Met to tumor progression and invasion.