Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma

Abstract

We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelialmesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the β6 integrin subunit and a consequent induction of αvβ6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-β and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of β6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of patients with high β6 expression. Elevated receptor expression did not simply reflect increasing tumor stage, since log-rank analysis showed a more significant impact on the survival of patients with early-stage, as opposed to late-stage, disease. Cox regression analysis confirmed that this integrin is an independent variable for these tumors. These findings define the αvβ6 integrin as an important risk factor for early-stage disease and a novel therapeutic candidate for colorectal cancer.

Integrin αvβ6 sets the stage for colorectal cancer metastasis

“…An interesting observation from this work was the additive effect of Ets-1 and αvβ6 expression on each other, wherein patients who were positive for both Ets-1 and αvβ6 expression relapsed earlier than patients who are positive for Ets-1 or αvβ6 alone [37]. These findings were supported by previous work by Bates et al who also demonstrated the transcriptional activation of β6 by Ets-1 correlated with poor patient survival [30]. Peng et al investigated the interplay between Ets-1 and αvβ6 expression on the 5-year survival rates of 158 patients from Qilu Hospital (Shandong University, China), though it is important to note that patients with elevated risk factors were encouraged to take adjuvant chemotherapy, of which 87 (55.1 %) received 5-fluorouracil (5-FU)-based adjuvant chemotherapy [37].…”

“…In terms of patient survival, the phenotypic transition from a lymph node negative Duke's stage B tumour to a nodal positive metastasis (Duke's stage C) is a crucial step in disease progression [40], and so this would be one likely transition where one might expect to observe upregulation of poor prognostic indicators [37,30]. As this was not the case in either study, it is possible that other pro-metastatic factors (e.g.…”

“…The steadily growing numbers of CRC deaths are a reminder that there remain unmet clinical needs for a greater understanding of the molecular biology of CRC metastasis, for the discovery/validation of prognostic biomarkers and the development of improved early detection methods. Several studies have linked expression of the β6 integrin subunit with a more aggressive, invasive cancer phenotype [24][25][26][28][29][30]. When bound to its sole binding partner αv, the β6 subunit is an epithelial cell-restricted antigen whose expression is elevated during tissue remodelling events (e.g.…”

“…Elevated β6 expression has been observed in many cancers, including CRC, gastric, ovarian, liver, thyroid, endometrial and cervical squamous carcinoma, where expression invariably correlates with poor patient survival [32,33]. Immunohistochemical studies have demonstrated elevated β6 expression negatively correlates with CRC patient survival [30], which was ascribed to be mediated through β6's roles in promoting cell proliferation, migration and invasion into proximal tissues eventually leading to metastasis [2,25,26,30,[33][34][35]. Previous studies have demonstrated that the liver metastases of CRC patients exhibit significantly elevated αvβ6 expression when compared to the primary colon cancer site and that those patients whose primary tumours were αvβ6-positive had a significantly increased rate of liver metastasis [36].…”

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

“…There is now overwhelming evidence for its role in the clinical progression of multiple human epithelial malignancies (colon, ovary, and brain), both from the in situ to the invasive stage as well as from the invasive stage to regional and distant metastasis 5, 6, 7. The addition of breast cancers to this long list of epithelial cancers where integrin α v β 6 plays a role in clinical progression is more recent.…”