RESUMO
High morbidity and mortality of cancer, especially colorectal cancer (CRC), in diabetic patients have been reported. In this study, we investigated the relationship between the presence of diabetes mellitus (blood hemoglobin A1C was 6.5% or higher at the time of diagnosis of CRC) and the progression and liver metastasis of CRC. Histopathological findings in the primary lesions, which were preferential to diabetes-complicated CRC (DM-CRC) and the liver metastasis, were also investigated. Of the 473 CRC patients who underwent curative surgical resection, 148 (31%) had diabetes. In DM-CRC cases, the stage was more advanced, with more cases in stage IV or postoperative disease recurrence. Histopathological findings correlated with liver metastasis in DM-CRC, including budding grade, perineural invasion, and myxomatous tumor stroma, and all were highly correlated with the stage. Additionally, myxomatous stroma showed the strongest correlation with liver metastasis in multivariate analysis. Myxomatous stroma in stage III cases correlated with liver recurrence. The myxomatous stroma was abundant in biglycan protein and contained numerous CD90-positive mesenchymal stem cells (MSCs). In human colon cancer cell line HT29, biglycan expression was induced by high sugar concentration, fatty acids, and insulin, and its contact co-culture with MSCs resulted in enhanced stemness and epithelial-mesenchymal transition phenotype. Thus, DM-CRC has higher malignant phenotypes compared to non-DM-CRC, and the involvement of diabetes-induced biglycan may act as a pathogenic factor.
RESUMO
The renin-angiotensin system (RAS) is implicated in the maintenance of blood pressure and in many other biological processes including tumorigenesis and metastasis formation. Angiotensin-II (A-II) type 2 receptor (AGTR2) seems to be involved in different types of cancer; its role, however, is still unclear. Here, we investigated the role of RAS, and specifically that of AGTR2, in oral squamous cell carcinoma (OSCC) progression. AGTR2 has opposite effect on vasodilation and blood pressure compared to AGTR1. In 23 OSCCs, we found that the AGTR1/AGTR2 mRNA ratio was inversely associated with disease progression, while nuclear AGTR2 positivity was associated with disease progression. In the human OSCC cell lines HSC3 and HSC4, AGTR1 was associated with proliferation and invasion, while AGTR2 was associated with anti-apoptosis and anti-oxidative stress. Levels of nuclear AGTR2 confirmed by subcellular fractionation increased in hypoxic and hyperglycemic conditions, in which apoptosis and oxidative stress were suppressed and the redox status altered to reduction. Accumulation of nuclear AGTR2 by inhibition of extranuclear transportation decreased apoptosis and increased proliferation and invasion in HSC3 cells. Intratumoral angiotensin-II (but not serum angiotensin-II) levels were associated with stage and nuclear AGTR2 positivity. In OSCC cell lines, intracellular angiotensin-II was produced by themselves. Notably, losartan, an angiotensin receptor blocker, inhibited intracellular angiotensin-II production and AGTR2 nuclear localization to enhance the antitumoral effect of 5-FU in an OSCC tumor model. While the precise role of nuclear AGTR2 requires further examination, these data suggest that the intracellular angiotensin system might be a significant target for OSCC.