Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions.

Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2α by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2α is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2α-regulated genes COX4I2 and ADORA2A. In contrast, HIF2α and HIF2α-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2α and HIF1α protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1α-target genes are almost exclusively overexpressed in VHL-mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2α in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1α-independent.

Blockage of Squamous Cancer Cell Collective Invasion by FAK Inhibition Is Released by CAFs and MMP-2.

Metastasis remains a clinically unsolved issue in cancer that is initiated by the acquisition of collective migratory properties of cancer cells. Phenotypic and functional heterogeneity that arise among cancer cells within the same tumor increase cellular plasticity and promote metastasis, however, their impact on collective cell migration is incompletely understood. Here, we show that in vitro collective cancer cell migration depends on FAK and MMP-2 and on the presence of cancer-associated fibroblasts (CAFs). The absence of functional FAK rendered cancer cells incapable of invading the surrounding stroma. However, CAFs and cancer cells over-expressing MMP-2 released FAK-deficient cells from this constraint by taking the leader positions in the invasive tracks, pushing FAK-deficient squamous cell carcinoma (SCC) cells towards the stroma and leading to the transformation of non-invasive cells into invasive cells. Our cell-based studies and the RNAseq data from the TCGA cohort of patients with head and neck squamous cell carcinomas reveal that, although both FAK and MMP-2 over-expression are associated with epithelial-mesenchymal transition, it is only MMP-2, not FAK, that functions as an independent prognostic factor. Given the significant role of MMP-2 in cancer dissemination, targeting of this molecule, better than FAK, presents a more promising opportunity to block metastasis.