Impact of HIF-1α, LOX and ITGA5 Synergistic Interaction in the Tumor Microenvironment on Colorectal Cancer Prognosis.

Abstract

Background: As colorectal cancers are histopathologically and molecularly highly heterogeneous tumors, it is necessary to consider the tumor's microenvironment as well as its cellular characteristics in order to determine the biological behavior of the tumor. This study included 100 patients who underwent resection for colorectal cancer. We aimed to investigate the relationships between the expression status of the HIF-1α, LOX and ITGA5 proteins and clinicopathologic parameters. Methods: HIF-1α, LOX and ITGA5 antibodies were applied immunohistochemically to tissue microarrays prepared from tumor samples. Expression status in the tumor microenvironment were evaluated using a combined scoring system based on staining intensity and the percentage of positively stained cells. Nuclear HIF-1α expression in tumor cells was quantified, with >1% considered positive. The staining of HIF-1α, ITGA5 and LOX was analyzed in relation to prognostic and molecular features. Results: The staining of HIF-1α, ITGA5 and LOX in the tumor microenvironment demonstrated a positive correlation with one another and with HIF-1α and LOX expression in tumor cells. In patients with KRAS, NRAS or BRAF mutation and the moderate to strong expression of all three of these proteins in the tumor microenvironment, the number of metastatic lymph nodes was higher than in other patients. Stage IV patients with the moderate to strong expression of HIF-1α, ITGA5 or LOX in the microenvironment had lower progression-free survival than those with weak expression (p < 0.05). In addition, female gender; moderate to strong HIF-1α, LOX and ITGA5 stromal expression; and metastatic first line chemotherapy only were found to be independently associated with an increased risk of progression. Conclusions: These markers may be useful in predicting treatment responses and may also guide the development of alternative or combined treatments that specifically target molecules such as HIF and LOX. Our study should be supported by more comprehensive studies addressing the tumor stroma and its prognostic importance.