Ding et al., pp. 1690–1694 When the Women's Health Initiative (WHI) recently reported that a large trial involving more than 36,000 postmenopausal women could not confirm that calcium and vitamin D supplementation prevents colorectal cancer, it came as a surprise. A beneficial role of calcium and vitamin D intake was suggested in smaller prospective studies before, and milk and dairy consumption are known to lower the risk of colorectal cancer. However, in prior studies, the protective effect of vitamin D was substantially stronger in lean individuals and those who exercise, two groups that are characterized by decreased estrogen levels. Ding and colleagues reanalyzed the data of the WHI study and found that hormonal replacement therapy is an important confounding factor in the analysis of the data. They report that calcium and vitamin D supplementation seems to be effective against colorectal cancer in women that are not on hormonal replacement therapy (HR = 0.71). In women taking estrogen alone or a combination of estrogen and progestin, the supplementation may slightly increase the risk. The authors discuss a variety of intricate interactions between the pathways that could explain these findings. Overall, the results suggest that calcium and vitamin D supplements should not be given at the same time as hormonal replacement therapy. Hazard ratio (HR) of colorectal cancer in response to calcium and vitamin D supplementation in 16,000 postmenopausal women assigned to factorial randomized estrogen treatments (E-only, estrogen only; E+P, estrogen and progestin). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] Baker et al., pp. 1695–1700 Transforming growth factor-beta (TGF-beta) is a multifunctional protein that induces differentiation and inhibits proliferation of epithelial cells in the gut. However, tumor cells are also influenced by the action of the cytokine, which is overexpressed in many advanced malignancies. Produced as a large precursor protein, it contains a pro-region (called latency-associated peptide or LAP) that is cleaved from the C terminus during maturation. Binding of the cytokine to the TGF-beta receptor induces phosphorylation of Smad 2 and/or Smad3, which then bind to Smad4 and translocate to the nucleus to modulate gene transcription. TGF-beta contains a signal sequence and is a secreted protein; however, a recent report identified a cell surface-bound form at the surface of regulatory T cells. In this issue of IJC, Baker and colleagues report that colorectal cancer cells also express membrane-bound TGF-beta, which is recognized by an antibody directed against the latent form of the protein. Latent TGF-beta is not known to be signaling-competent; nevertheless, the authors tested whether TGF-beta bound at the surface of cancer cells could initiate signaling. They found that cell-bound TGF-beta induced phosphorylation of Smad2 in other cancer cells and intraepithelial CD8+ T cells in coculture experiments. The authors speculate that active cell surface-associated TGF-beta could provide a paracrine stimulus to neighboring tumor cells and at the same time contribute to immunosuppression within the tumor microenvironment. Heinlein et al., pp. 1701–1709 It is quite unusual that 75% of all mutations in the p53 tumor suppressor gene comprise missense point mutations. In contrast, other tumor suppressors are inactivated by gene truncation, deletion or promoter silencing. This observation is compatible with the model that missense point mutations in the p53 gene provide a selective growth advantage for the tumor. Heinlein and colleagues report on a mouse model that supports this “gain of function” role of p53 in carcinoma. The authors used a transgenic mouse model for mammary adenocarcinoma based on BALB/c mice that carry the SV40 early gene region under the control of a mammary epithelial cell-specific promoter (WAP-T mice). As a consequence of transgene expression, these mice develop multifocal intraepithelial neoplasia, which can progress to invasive, but rarely metastatic mammary carcinoma. The model represents a p53 “loss of function” setting as the SV40 T-Ag functionally compromises the endogenous p53 protein. To assess the effects of mutated p53 on tumor progression, the authors constructed transgenic mice expressing a mutated p53, also under the control of the WAP-promoter and crossed it to WAP-T mice. They found that mutant p53 (R270H) in double-transgenic mice enhanced the transition from intraepithelial neoplasia to invasive carcinoma. This resulted in a higher frequency of invasive carcinoma per gland and per mouse, a more severe tumor phenotype, and more frequent pulmonary metastasis. These observations demonstrate a novel and important role for “gain of function” mutations of p53 in carcinogenesis.
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Jul 17, 2018
Jana Majerska + 3
Open Access
