The tumor microenvironment of colorectal cancer: stromal TLR-4 expression as a potential prognostic marker.

BACKGROUND: Colorectal cancer can be efficiently treated when found at early stages, thus the search for novel markers is of paramount importance. Since inflammation is associated with cancer progression and angiogenesis, we investigated expression of cytokines like IL-6 and other mediators that play a key role in the innate immune system, in particular toll like receptor 4 (TLR4), in the microenvironment of lesions from different stages of colon disease progression, from ulcerative colitis to adenoma and adenocarcinoma to find useful markers. METHODS: The presence of inflammatory cells and expression of key cytokines involved in the inflammation process were quantified by immunohistochemistry in specific tissue compartments (epithelial, stromal, endothelial) by immunohistochemistry. A murine azoxymethane/dextran sulfate model in which Tir8, a negative regulator of the inflammatory response, was ablated was used to confirm the clinical observations. 116 Archival tissue samples from patients with different stages of colorectal disease: 13 cases of ulcerative colitis (UC), 34 tubular or tubulo-villous adenomas (AD), and 53 infiltrating adenocarcinomas. 16 specimens of healthy mucosa surgically removed with the cancerous tissue were used as a control. RESULTS: The differences between healthy tissues and the diverse lesions was characterized by a marked inflammatory-angiogenic reaction, with significantly (P < 0.05) higher numbers of CD68, CD15, and CD31 expressing cells in all diseased tissues that correlated with increasing grade of malignancy. We noted down-regulation of a potential modulator molecule, Hepatocyte Growth Factor, in all diseased tissues (P < 0.05). TLR-4 and IL6 expression in the tumor microenvironment were associated with adenocarcinoma in human samples and in the murine model. We found that adenocarcinoma patients (pT1-4) with higher TLR-4 expression in stromal compartment had a significantly increased risk in disease progression. In those patients with a diagnosis of pT3 (33 cases) colon cancer, those with very high levels of TLR-4 in the tumor stroma relapsed significantly earlier than those with lower expression levels. CONCLUSIONS: These data suggest that high TLR-4 expression in the tumor microenvironment represents a possible marker of disease progression in colon cancer.

Capecitabine in breast cancer: the issue of cardiotoxicity during fluoropyrimidine treatment.

Capecitabine is an orally available fluoropyrimidine carbamate that selectively delivers fluorouracil (5-FU) to tissues expressing high levels of thymidine phosphorylase (TP) such as tumors. The drug has demonstrated efficacy in metastatic breast cancer, colorectal, and pancreatic cancer. Although these are considered safe drugs, a growing body of literature reports adverse cardiac effects. Clinical trials indicate that capecitabine has a cardiac toxicity similar to that of infused fluoropyrimidines such as 5-FU. Here, we review cardiotoxicity in the use of fluoropyrimidines, with particular attention toward capecitabine. We also describe a severe, reversible cardiac event that occurred in a 39-year-old woman, with no cardiac risk factors, treated with capecitabine for advanced breast cancer. This review and our experience confirm that fluoropyrimidine cardiotoxicity is an infrequent but documented side effect. Oncology patients under treatment should be closely observed and monitored for cardiac symptoms with particular attention in case of signs or symptoms of cardiovascular complications. The implementation of cardio-oncology interdisciplinary teams should, in the future, reduce the impact of cancer treatment-associated cardiotoxicity syndromes.