Mechanisms of radioresistance and the underlying signaling pathways in colorectal cancer cells.

Radiotherapy is one of the most common modalities for the treatment of a wide range of tumors, including colorectal cancer (CRC); however, radioresistance of cancer cells remains a major limitation for this treatment. Following radiotherapy, the activities of various cellular mechanisms and cell signaling pathways are altered, resulting in the development of radioresistance, which leads to therapeutic failure and poor prognosis in patients with cancer. Furthermore, even though several inhibitors have been developed to target tumor resistance, these molecules can induce side effects in nontumor cells due to low specificity and efficiency. However, the role of these mechanisms in CRC has not been extensively studied. This review discusses recent studies regarding the relationship between radioresistance and the alterations in a series of cellular mechanisms and cell signaling pathways that lead to therapeutic failure and tumor recurrence. Our review also presents recent advances in the in vitro/in vivo study models aimed at investigating the radioresistance mechanism in CRC. Furthermore, it provides a relevant biochemical basis in theory, which can be useful to improve radiotherapy sensitivity and prolong patient survival.

TGF-ß acts as a dual regulator of COX-2/PGE2 tumor promotion depending of its cross-interaction with H-Ras and Wnt/ß-catenin pathways in colorectal cancer cells.

Transforming growth factor-ß (TGF-ß) plays a dual role acting as tumor promoter or suppressor. Along with cyclooxygenase-2 (COX-2) and oncogenic Ras, this multifunctional cytokine is deregulated in colorectal cancer. Despite their individual abilities to promote tumor growth and invasion, the mechanisms of cross regulation between these pathways is still unclear. Here, we investigate the effects of TGF-ß, Ras oncogene and COX-2 in the colorectal cancer context. We used colon adenocarcinoma cell line HT-29 and Ras-transformed IEC-6 cells, both treated with prostaglandin E2 (PGE2 ), TGF-ß or a combined treatment with these agents. We demonstrated that PGE2 alters the subcellular localization of E-cadherin and ß-catenin and enhanced the tumorigenic potential in HT-29 cells. This effect was inhibited by TGF-ß, indicating a tumor suppressor role. Conversely, in Ras-transformed IEC-6 cells, TGF-ß induced COX-2 expression and increased invasiveness, acting as a tumor promoter. In IEC-6 Ras-transformed cells, TGF-ß increased nuclear ß-catenin and Wnt/ß-catenin activation, opposite to what was seen in the PGE2 and TGF-ß joint treatment in HT-29 cells. Together, our findings show that TGF-ß increases COX-2 levels and induces invasiveness cooperating with Ras in a Wnt/ß-catenin activation-dependent manner. This shows TGF-ß dual regulation over COX-2/PGE2 tumor promotion depending on the H-Ras and Wnt/ß-catenin pathways activation status in intestinal cancer cells.

Annexin A2 overexpression associates with colorectal cancer invasiveness and TGF-ß induced epithelial mesenchymal transition via Src/ANXA2/STAT3.

Annexin A2 (ANXA2) is upregulated in several malignancies, including colorectal cancer (CRC). However, there is little knowledge on the molecular mechanisms involved to its upregulation. The aim of this study was to identify the mechanism through which ANXA2 overexpression leads to CRC progression and evaluate its potential prognostic value. We used human CRC samples to analyse the correlation between ANXA2 levels and tumour staging. ANXA2 expression was increased in CRC tissues compared to normal colon tissues. In addition, we observe increased ANXA2 levels in stage IV tumours and metastasis, when compared to stage I-III. Whereas E-cadherin, an epithelial marker, decreased in stage II-IV and increased in metastasis. We've also shown that TGF-ß, a classic EMT inductor, caused upregulation of ANXA2, and internalization of both E-cadherin and ANXA2 in CRC cells. ANXA2 silencing hindered TGF-ß-induced invasiveness, and inhibitors of the Src/ANXA2/STAT3 pathway reversed the EMT. In silico analysis confirmed overexpression of ANXA2 and association to the consensus moleculars subtypes (CMS) with the worst prognosis. Therefore, ANXA2 overexpression play a pivotal role in CRC invasiveness through Src/ANXA2/STAT3 pathway activation. The association of ANXA2 to distinct CMSs suggests the possible use of ANXA2 as a prognostic marker or directed target therapy.