Hypoxia induces hemorrhagic transformation in pituitary adenomas via the HIF-1α signaling pathway

Abstract

Abstract. The hypoxia inducible factor 1 α (HIF-1α) activity has been associated with various hemorrhagic events. The biological role of HIF-1α in the hemorrhagic transformation of pituitary adenomas remains unknown. We hypothesized that fast growing tumor cells tend to predispose themselves to sublethal hypoxia and activate the HIF-1α signaling pathway, leading to hemorrhagic transformation in pituitary adenomas. Here, we used apoplectic and non-apoplectic pituitary adenomas to determine the involvement of HIF-1α signaling in intratumoral hemorrhage. We employed HIF-1α overexpression/knockdown strategies to examine the association between HIF-1α signaling and hemorrhagic presentation in vitro and in vivo. In support of our hypothesis, compared with nonhemorrhagic pituitary adenomas, higher cellular proliferation was observed in hemorrhagic ones and it correlated with increased HIF-1α signaling. HIF-1α overexpression activated its downstream genes, vascular endothelial growth factor and the proapoptotic BNIP3, in MMQ pituitary adenoma cells and this up-regulation was attenuated by HIF-1 siRNA. In vivo studies using MMQ cell xenografts in nude mice showed that HIF-1α overexpression significantly promoted hemorrhagic transformation. Our study indicates that tumor hypoxia, following rapid tumor growth, may promote hemorrhagic transformation in pituitary adenomas via the HIF-1α signaling pathway.

Molecular Network Basis of Invasive Pituitary Adenoma: A Review

“…More than a decade ago, the apoptotic protective function of HIF-1α in human pituitary adenoma cell line HP75 under hypoxic conditions via a knockdown experiment was observed (26). VEGF was then confirmed to be activated by HIF-1α (27), but the HIF-1α overexpression model of rodent MMQ cell culture showed a higher apoptotic rate compared with the control, which contradicted the results of knockdown experiments in the human cell line. RWD-containing sumoylation enhancer (RSUME), a stabilizer of HIF-1α under hypoxia (28), is reported to upregulate VEGF in vitro , substantiating the interaction between HIF-1α and VEGF (29).…”

Analysis of Tumor Angiogenesis and Immune Microenvironment in Non-Functional Pituitary Endocrine Tumors

“…Xiao et al demonstrated rapid and hemorrhagic transformation in PitNETs via the HIF-1α hypoxic signaling pathway [35]. Interestingly, there was no significant correlation in the expression levels of HIF-1α and VEGF mRNA in PitNETs, although VEGF-A is mainly induced by HIF-1α [35].…”

Role of a p53 polymorphism in the development of nonfunctional pituitary adenomas

“…We then assessed the impact of the R72 variant on the ability of pituitary adenoma cells to adapt to the hypoxia that arises as an adenoma reaches critical size (Xiao et al, 2011). We investigated two biological mechanisms that can allow cells from tumors like pituitary adenomas to adapt to hypoxia: increased VEGF, which drives angiogenesis, and increased glycolysis, the anaerobic metabolism upregulated by tumor cells to adapt to hypoxia as part of the Warburg effect.…”