Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer.

Colon cancer development and malignant progression are driven by genetic and epigenetic alterations in tumor cells and by factors from the tumor microenvironment. Cancer cells become reliant on the activity of specific oncogenes and on prosurvival and proliferative signals they receive from the abnormal environment they create and reside in. Accordingly, the response to anticancer therapy is determined by genetic and epigenetic changes that are intrinsic to tumor cells and by the factors present in the tumor microenvironment.

The Role of STAT1 for Crosstalk between Fibroblasts and Colon Cancer Cells.

Signaling between tumor cells and the associated stroma has an important impact on cancer initiation and progression. The tumor microenvironment has a paradoxical role in tumor progression and fibroblasts, a major component of the tumor stroma, have been shown to either inhibit or promote cancer development. In this study, we established that normal intestinal fibroblasts activate STAT1 signaling in colon cancer cells and, in contrast to cancer-associated fibroblasts, inhibit growth of tumor cells.

Activating mutations in β-catenin in colon cancer cells alter their interaction with macrophages; the role of snail.

Background: Tumor cells become addicted to both activated oncogenes and to proliferative and pro-survival signals provided by the abnormal tumor microenvironment. Although numerous soluble factors have been identified that shape the crosstalk between tumor cells and stroma, it has not been established how oncogenic mutations in the tumor cells alter their interaction with normal cells in the tumor microenvironment.

Principal Findings: We showed that the isogenic HCT116 and Hke-3 cells, which differ only by the presence of the mutant kRas allele, both stimulate macrophages to produce IL1β.

Tumor associated macrophages protect colon cancer cells from TRAIL-induced apoptosis through IL-1beta-dependent stabilization of Snail in tumor cells.

Background: We recently reported that colon tumor cells stimulate macrophages to release IL-1beta, which in turn inactivates GSK3beta and enhances Wnt signaling in colon cancer cells, generating a self-amplifying loop that promotes the growth of tumor cells.

Principal Findings: Here we describe that macrophages protect HCT116 and Hke-3 colon cancer cells from TRAIL-induced apoptosis. Inactivation of IL-1beta by neutralizing IL-1beta antibody, or silencing of IL-1beta in macrophages inhibited their ability to counter TRAIL-induced apoptosis.

The NF-κB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1β.

Progression of colon cancer from microadenoma to macroscopic tumors is coupled to augmentation of canonical Wnt signaling. We recently reported that tumor associated macrophages, through interleukin 1β (IL-1β) dependent phosphorylation of GSK3β, promote Wnt signaling in colon cancer cells, demonstrating that proinflammatory cytokines can enhance TCF4/β-catenin transcriptional activity in tumor cells. Here we investigated the pathway whereby IL-1β inactivates GSK3β and promotes Wnt signaling in colon cancer cells.

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: the role of p53 and p21.

Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele.

HDAC2 deficiency sensitizes colon cancer cells to TNFalpha-induced apoptosis through inhibition of NF-kappaB activity.

HDAC inhibitors exert potent anti-tumorigenic and anti-inflammatory activity. Their effects are selective for transformed cells, and we recently demonstrated that transformation of epithelial cells with k-Ras sensitizes cells to HDACi induced apoptosis. The aim of this study was to determine whether the ability of HDACi to modulate signaling by a major pro-inflammatory cytokine, TNFalpha, is also restricted to cells that harbor mutant k-Ras.

Upregulation of Slc39a10 gene expression in response to thyroid hormones in intestine and kidney.

A novel zinc transporter has been purified and cloned from rat renal brush border membrane. This transporter was designated as Zip10 encoded by Slc39a10 gene and characterized as zinc importer. Present study documents the impact of thyroid hormones on the expression of Zip10 encoded by Slc39a10 gene in rat model of hypo and hyperthyroidism.

Chronic cold stress-induced alterations in brush border membrane composition and enzyme activities in rat intestine.

The effect of chronic cold stress on the composition and function of rat intestinal brush border membrane (BBM) was studied. Various lipid fractions from intestinal BBM viz. cholesterol (p < 0.