Carcinomas form tumors in which malignant epithelial cells intermingle with nonmalignant stromal cells; indeed, stromal cells may constitute the majority of cells in the tumor. Moreover, bidirectional interactions between cancer cells and their microenvironment may influence tumor progression (see Bierie and Moses). Noting that mutations of the tumor suppressor p53 have been found in tumor stroma, Hill et al. investigated cancer cell-stromal interactions in a transgenic mouse model of prostate cancer in which a fragment of the SV40 large T antigen is expressed in prostate epithelium in response to androgens at puberty (TgAPT121 mice) to inactivate retinoblastoma (Rb) protein function. When TgAPT121 mice were crossed with wild-type, p53 null, or p53 heterozygous mice, p53 loss facilitated tumor progression. Tumors emerged earlier in p53 null than in p53 heterozygous mice and earlier in p53 heterozygous than in p53 wild-type mice. Tumors in mice lacking p53 were massive and had an extensive mesenchymal component; such "stromal tumors" appeared much later in 44% of wild-type p53 mice. Whereas all TgAPT121 prostates showed enhanced epithelial cell proliferation before tumor development, only mice also lacking p53 showed enhanced fibroblast proliferation in mesenchyme shortly (two months) after T121 induction. Immunofluorescence analysis revealed that, whereas p53 was undetectable in the prostates of wild-type mice, p53 was expressed in the epithelial cells and a subset of mesenchymal cells in TgAPT121mice two months after T121 induction. Loss of p53 expression was apparent in regions of mesenchymal proliferation of emerging tumors, and laser capture microdissection of stromal regions of TgAPT121;p53+/– or TgAPT121;p53+/+ tumors confirmed loss of p53 in proliferating stroma. Thus, the authors propose that the abnormally proliferating epithelial cells stimulate p53 expression in mesenchymal cells through paracrine interactions. Because lack of p53 is associated with enhanced proliferation, this leads to a selective pressure for p53 loss in the mesenchyme, enhanced stromal proliferation, and massive tumor growth.
R. Hill, Y. Song, R. D. Cardiff, T. Van Dyke, Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell 123, 1001-1011 (2005). [PubMed]
B. Bierie, H. L. Moses, Under pressure: Stromal fibroblasts change their ways. Cell 123, 985-987 (2005). [PubMed]