5. that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2, an element of the oxygen-sensing machinery. Inhibition of HIF-2 prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and nonsmall-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2 exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2 oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2 as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells. Keywords:epidermal growth factor receptor, growth signaling, hypoxia-inducible factor, insulin-like growth factor receptor, oncogene Cancer is caused by a succession of genotypic changes that confer cells with six rate-limiting traits, coined the hallmarks of cancer, required for tumorigenesis (1). These hallmarks include the ability to proliferate in a growth signal-independent manner, evade antigrowth and proapoptotic signals, induce new blood vessel formation, Rabbit Polyclonal to ALK and invade surrounding tissues. The latter attributes essential for tumor progression are largely dependent on physiological parameters and thus involve more widespread mechanisms. In contrast, cell autonomous proliferative capability, the first hallmark of cancers, is acquired through the genetic activation of any number of dominant oncogenes or inactivation of tumor suppressor genes (2). These complexities are amplified by emerging evidence that multiple redundant signaling pathways can be activated within a single cancer (3,4). As such, the current belief is that cancer cells evolve in a parallel manner to attain growth autonomy, and any attempts at antagonizing these pathways would be restricted to cancers with defined mutational profiles. The phenomena referred to as oncogene addiction and tumor suppressor gene hypersensitivity further substantiate that various genetic alterations can confer a selective growth advantage to mutant cells. The oncogene addiction theory contends that, despite the myriad of genetic aberrations observed in an individual cancer, disruption of a central oncogenic pathway would cause growth inhibition and likely tumor regression (5). It has, for instance, been demonstrated that continued expression Acalisib (GS-9820) ofKRASandMYCare required for maintenance of the tumorigenic state in lung tumors and osteogenic sarcomas induced by the corresponding oncogenes (6,7). The efficacy of agents targeting BCR/ABL and HER-2 in patients with chronic myeloid Acalisib (GS-9820) leukemia and breast carcinomas, respectively, similarly provides important clinical evidence that human cancers may rely wholly on a single gene, and the specific pathways it impinges on, to sustain tumor growth (8,9). Restoration of tumor suppressor function has also been shown to inhibit cancer cell growth. A classic example of this is the reintroduction of a wild-type copy of the von Acalisib (GS-9820) Hippel-Lindau (VHL) tumor suppressor gene in clear cell renal carcinoma (RCC) (10). In this model system, loss of VHL results in the constitutive stabilization of the hypoxia-inducible factor (HIF) and its subsequent activation of the circuits that drive RCC tumorigenesis (1114). The HIF-2 isoform in particular promotes autocrine growth signaling and cell cycle progression via epidermal growth factor receptor (EGFR) and c-Myc-dependent mechanisms (15,16). Expression of HIF is not, of course, unique to RCC and is observed in the vast majority of overt carcinomas (17). In addition to being the primary cellular response to hypoxia, HIF activation is endorsed by many oncogene and tumor suppressor gene pathways that increase its synthesis or stability.