Hepsin paradox reveals unexpected complexity of metastatic process.
The existing models of cancer progression assume that a linear sequence of genetic and epigenetic events occurs during this process. In this representation every new event (either loss of a tumor-suppressor, or activation of a proto-oncogene) makes cells even more malignant. The result is a "super" cell that can form metastases at the distant sites. Metastatic cells are believed to carry all genetic and epigenetic characteristics that are necessary for metastasis formation. Recently, we have shown that cell-surface protease hepsin causes disorganization of the basement membrane and promotes prostate cancer progression and metastasis. In human prostate cancer hepsin is upregulated in the precancerous lesions and this upregulation is maintained in the primary tumors. Remarkably and completely unexpected for a metastasis-promoting gene, hepsin is expressed at low levels in metastatic lesions and the message is completely absent in metastasis-derived prostate cancer cell lines. These results demonstrate that genes that play an important role in metastatic process may exercise their role only at the specific fragments of cancer progression pathway (for example, during initial invasion and tissue disorganization in the primary organ) and may have no role in metastatic lesions. Future treatment of cancer patients may rely heavily on monitoring of tumor progression, as treatment efficient in attenuation of initial tumor progression may be inefficient or even adverse at the advance stages of disease.
Vasioukhin
Valeri
V
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. vvasiouk@fhcrc.org
D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics; D000090063:Proto-Oncogene Mas; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012697:Serine Endopeptidases; C055645:hepsin