Combined expression of HIF1α, VEGF and HER2 predicts metastasis, relapse and response to combination chemotherapy in colorectal cancer patients

Cancer variability is the primary source of relapse and treatment failure. Hence, determining the optimal chemotherapeutic regime for a given cancer type is an important research topic. Evaluation of simultaneous expression of target molecules is essential to choose the optimal combination therapy for each colorectal cancer patient. Angiogenesis presents a potential target in colorectal cancer treatment. This process is necessary for cancer metastasis, which is the main reason of CRC mortality. This phenomenon was stimulated by pro-angiogenic factors including vascular endothelial growth factor (VEGF). Prognostic and predictive significance of VEGF remains controversial. Thus, some reports showed that its overexpression was significantly related to poor prognosis and short survival in colorectal cancer patients [1]. Others demonstrated that VEGF has any meaningful prognostic role [2]. Recently, further study has reported that elevated level of VEGF-A is correlated to longer metastatic overall survival in patients with metastatic colorectal cancer receiving bevacizumab therapies [3]. Yin et al indicated that VEGF were overexpressed in both primary and matched metastatic tissues of CRC [4].

Another essential mediator of angiogenesis is hypoxia inducible factor 1α (HIF1α). Hypoxia is important for both tumor growth and metastasis. Due to its major role in cell death resistance, metabolism alteration, angiogenesis, and metastasis, HIF1α may present an attractive target for antitumor therapy [5] [6] [7]. The HIF-1α protein is overexpressed in a variety of human cancers [8]. In CRC, its overexpression is frequently associated to angiogenesis, metastasis, apoptosis disruption and chemo-resistance [9].

Human epidermal growth factor receptor 2 (HER2) is a cell surface protein of the EGFR family with an essential role regarding diagnostic and prognosis in several cancers, especially in breast cancer. According to Kumar et al, HER2 overexpression was associated to angiogenesis and VEGF expression in breast cancer [10]. However, both its angiogenic potential and prognostic significance remain controversial in colorectal cancers [11]. Furthermore, retrospective studies showed that HER2 amplification could be seen as a potential therapeutic target in CRC [12,13]. Drug resistance is an essential cause of treatment failure. Previous research studies have suggested that chemoresistance to cancer agents might be associated with HIF-1α [[14], [15], [16]]. Currently, there are still very few studies which have focused on colorectal cancer in south Tunisia, among them our previous study [17]. The aim of this study was to assess the simultaneous expression of HIF1α, HER2 and VEGF, its prognostic impact and its response to chemotherapy of Tunisian colorectal cancer patients.

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