Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis.
Our understanding of cancer has largely come from the analysis of aberrations within the tumor cell population. Yet it is increasingly clear that the tumor microenvironment can significantly influence tumorigenesis. For example, the mesenchyme can support the growth of tumorigenic epithelium. However, whether fibroblasts are subject to genetic/epigenetic changes as a result of selective pressures conferred by oncogenic stress in the epithelium has not been experimentally assessed. Recent analyses of some human carcinomas have shown tumor-suppressor gene mutations within the stroma, suggesting that the interplay among multiple cell types can select for aberrations nonautonomously during tumor progression. We demonstrate that this indeed occurs in a mouse model of prostate cancer where epithelial cell cycle disruption via cell-specific inhibition of pRb function induces a paracrine p53 response that suppresses fibroblast proliferation in associated stroma. This interaction imposes strong selective pressure yielding a highly proliferative mesenchyme that has undergone p53 loss.
Hill
Reginald
R
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Song
Yurong
Y
Cardiff
Robert D
RD
Van Dyke
Terry
T
D000199:Actins / Q000032:analysis; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D049109:Cell Proliferation; D003238:Connective Tissue / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D005838:Genotype; D053533:Keratin-8; D007633:Keratins / Q000032:analysis; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D019899:Paracrine Communication; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000032:analysis; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D000199:Actins; D000952:Antigens, Polyomavirus Transforming; D053533:Keratin-8; C486595:Krt8 protein, mouse; D016160:Retinoblastoma Protein; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D016159:Tumor Suppressor Protein p53; D007633:Keratins