Su2032 Differential Early Metabolic Changes in Colon Carcinogenesis for Health Disparities: Physiological and Molecular Evidence

Abstract

Background: Epidemiologic data unequivocally demonstrate a 23% higher incidence in colonic neoplasia in blacks with concomitant 50% increase in colorectal (CRC) mortality compared to whites. However, the biological basis for this has been largely unexplored. The role of early metabolic alterations such as the Warburg effect is clearly appreciated in established cancers however it is not known in early neoplasia. Given that metabolic CRC risk factors (i.e. diabetes, obesity) disproportionately impact blacks, we used polarizationgated spectroscopy (PGS) to examine the microvascular blood flow as a surrogate of metabolic dysregulation in early neoplastic transformation. To explore potential molecular correlates behind PGS, we chose to investigate two master regulators of early CRC, Sirt 6 and Hif-1α, which couple metabolic dysregulation (Sebastian et al., Cell 2012). Methods: For this study we used a fiberoptic PGS probe to measure oxyhemoglobin (OHb) and deoxyhemoglobin (DHb) within rectal microvasculature in 80 prospectively recruited black patients. We compared results to a previous cohort of ~120 white patients in the superficial mucosa (~150μm). We assessed Sirt 6 and Hif-1α expression from rectal biopsies of 80 patients by RT-PCR. Field carcinogenesis was defined as presence of molecular changes in advanced adenomas (AAs) evident elsewhere in the colon. Results: In blacks, there was a striking induction in DHb (220% of control) with OHb being more muted (150% of control). Thus, from a diagnostic perspective, DHb appears to be a stronger marker than OHb. This was in contradistinction to whites, where only OHb was statistically significant with diagnostic potential. The molecular basis of this finding was supported by metabolic regulators, Sirt 6 and Hif-1α, in blacks. The reduced expression of Sirt6 mRNA (Figure 1) appears to give a marked induction of Hif-1α mRNA(Figure 2). Conclusions: We demonstrate herein, for the first time, that there differential metabolic changes in blacks than whites. This was supported physiologically with differential diagnostic effects of DHb versus OHb which implies altered oxygen extraction consonant with Warburg effect. The molecular underpinnings may be related to the key metabolic sensor, Sirt 6 through control of Hif-1α. This work provides potentially important insights into the pathogenesis of CRC disparities and demonstrates the power of optical spectroscopy provide physiological common denominator of the myriad of complex molecular alterations in early carcinogenesis.