The cancer matrisome: From comprehensive characterization to biomarker discovery.

Tumor progression and dissemination critically depend on support from the tumor microenvironment, the ensemble of cellular and acellular components surrounding and interacting with tumor cells. The extracellular matrix (ECM), the complex scaffolding of hundreds of proteins organizing cells in tissues, is a major component of the tumor microenvironment. It orchestrates cellular processes including proliferation, migration, and invasion, that are highly dysregulated during cancer progression. Alterations in ECM abundance, integrity, and mechanical properties have been correlated with poorer prognosis for cancer patients. Yet the ECM proteome, or "matrisome," of tumors remained until recently largely unexplored. This review will present the recent developments in computational and proteomic technologies that have allowed the comprehensive characterization of the ECM of different tumor types and microenvironmental niches. These approaches have resulted in the definition of protein signatures distinguishing tumors from normal tissues, tumors of different stages, primary from secondary tumors, and tumors from other diseased states such as fibrosis. Moreover, recent studies have demonstrated that the levels of expression of certain genes encoding ECM and ECM-associated proteins is prognostic of cancer patient survival and can thus serve as biomarkers. Last, proteomic studies have permitted the identification of novel ECM proteins playing functional roles in cancer progression. Such proteins have the potential to be exploited as therapeutic targets.

Cell-specific regulation of L-WNK1 by dietary K.

Flow-induced K(+) secretion in the aldosterone-sensitive distal nephron is mediated by high-conductance Ca(2+)-activated K(+) (BK) channels. Familial hyperkalemic hypertension (pseudohypoaldosteronism type II) is an inherited form of hypertension with decreased K(+) secretion and increased Na(+) reabsorption. This disorder is linked to mutations in genes encoding with-no-lysine kinase 1 (WNK1), WNK4, and Kelch-like 3/Cullin 3, two components of an E3 ubiquitin ligase complex that degrades WNKs. We examined whether the full-length (or "long") form of WNK1 (L-WNK1) affected the expression of BK α-subunits in HEK cells. Overexpression of L-WNK1 promoted a significant increase in BK α-subunit whole cell abundance and functional channel expression. BK α-subunit abundance also increased with coexpression of a kinase dead L-WNK1 mutant (K233M) and with kidney-specific WNK1 (KS-WNK1), suggesting that the catalytic activity of L-WNK1 was not required to increase BK expression. We examined whether dietary K(+) intake affected L-WNK1 expression in the aldosterone-sensitive distal nephron. We found a paucity of L-WNK1 labeling in cortical collecting ducts (CCDs) from rabbits on a low-K(+) diet but observed robust staining for L-WNK1 primarily in intercalated cells when rabbits were fed a high-K(+) diet. Our results and previous findings suggest that L-WNK1 exerts different effects on renal K(+) secretory channels, inhibiting renal outer medullary K(+) channels and activating BK channels. A high-K(+) diet induced an increase in L-WNK1 expression selectively in intercalated cells and may contribute to enhanced BK channel expression and K(+) secretion in CCDs.