Selection of p53-Deficient Stromal Cells in the Tumor Microenvironment.

The tumor microenvironment is considered pro-oncogenic for reasons that, among others, involve the stimulation of cancer cell growth. However, little is known regarding how the tumor microenvironment affects the proliferation of stromal cells that coexist with cancer cells in the tumors. In the present study, we show that cancer cells trigger a paracrine response in normal fibroblasts that is not consistently mitogenic but may also become antimitogenic, inhibiting fibroblasts' proliferation in vitro.

TGF-β1, Smad-2/-3, Smad-1/-5/-8, and Smad-4 signaling factors are expressed in ameloblastomas, adenomatoid odontogenic tumors, and calcifying cystic odontogenic tumors: an immunohistochemical study.

Objectives: The TGF-β/Smad signaling pathway regulates diverse cellular functions, including tooth development, and is involved in numerous pathological processes such as tumorigenesis. The aim of this study was to investigate the immunoexpression of the TGF-β/Smad signaling pathway members in ameloblastoma (AM), calcifying cystic odontogenic tumor (CCOT), and adenomatoid odontogenic tumor (AOT).

Materials And Methods: This retrospective cross-sectional study included 65 tissue specimens: 34 AMs, 13 CCOTs, and 18 AOTs.

p21/waf1 and smooth-muscle actin α expression in stromal fibroblasts of oral cancers.

Background: Concerted alterations between stromal fibroblasts and neoplastic cells underline the carcinogenic process. Activation of alpha-smooth muscle actin (SMA) expression, a cytoskeleton protein normally expressed only in myoepithelial cells, is considered a landmark for the activation of stromal fibroblasts with little however being known regarding the mechanism governing the expression of SMA in the stroma.

Methods: We have evaluated by immunohistochemistry the expression of SMA in the stroma of oral malignant and pre-malignant lesions, in association with the expression of p53 and p21 tumor suppressors that were shown previously to be deregulated and/or mutated in stromal fibroblasts of various cancers.

p21/waf1 and smooth-muscle actin α expression in stromal fibroblasts of oral cancers.

Background: Concerted alterations between stromal fibroblasts and neoplastic cells underline the carcinogenic process. Activation of alpha-smooth muscle actin (SMA) expression, a cytoskeleton protein normally expressed only in myoepithelial cells, is considered a landmark for the activation of stromal fibroblasts with little however being known regarding the mechanism governing the expression of SMA in the stroma.

Methods: We have evaluated by immunohistochemistry the expression of SMA in the stroma of oral malignant and pre-malignant lesions, in association with the expression of p53 and p21 tumor suppressors that were shown previously to be deregulated and/or mutated in stromal fibroblasts of various cancers.

Regulation of tumor-stromal fibroblast interactions: implications in anticancer therapy.

Recent advances in tumor biology have identified the stroma as an important regulator of carcinogenesis and potentially a valuable therapeutic target. While however the fact that by targeting the stromal component of a tumor represents a potential therapeutic strategy has been established, the knowledge for specific regulators for such interactions remains poor. The latter is largely due to the fact that appropriate methodological approaches that permit the screening for such regulators are lacking.

Expression of p21waf1/Cip1 in stromal fibroblasts of primary breast tumors.

During carcinogenesis, stromal fibroblasts undergo certain changes in concert with their neoplastic neighbors, an interaction that progressively leads to a cancer-associated state. However, despite the increasing appreciation of the importance of stromal/tumor interactions in the progression of cancer, little is known about the factors responsible for regulating the crosstalk between stromal fibroblasts and neoplastic cells. Here we show that the stage of the disease in primary human breast lesions affects p21 expression in the fibroblasts.

P53 mutations in stromal fibroblasts sensitize tumors against chemotherapy.

The efficacy of chemotherapy is usually viewed as the outcome of cancer-cell-autonomous processes while the contribution of stroma is being overseen. Here we show that p53 mutations in stromal fibroblasts, a genetic lesion that is detectable in primary breast, prostate and probably other cancers, while they accelerate tumorigenesis they also sensitize tumours against conventional chemotherapy by doxorubicin and cis-platinum. The mechanism by which p53 of stromal fibroblasts affects the response of a tumour against chemotherapy is likely to involve the induction of senescence in the fibroblasts which in turns results in the production of growth factors acting onto the cancer cells by paracrine mechanisms.

Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis.

Prostate, breast, and probably other epithelial tumors harbor inactivating mutations in the p53 tumor suppressor gene in the stromal cells, implying the nonautonomous action of p53 in carcinogenesis. We have tested this hypothesis by evaluating the tumorigenicity of MCF7 human breast cancer cells in severe combined immunodeficient mice that differ in their p53 status. Our results showed that, indeed, p53 ablation in the hosts reduced the latency for the development of MCF7 tumors.