Determination of Angptl4 mRNA as a Diagnostic Marker of Primary and Metastatic Clear Cell Renal-Cell Carcinoma

Abstract

BackgroundWe have previously shown that angiopoietin-like 4 (angptl4) mRNA, a hypoxia-inducible gene, is highly expressed in clear cell renal-cell carcinoma (ccRCC), the most common subtype of RCC for which no specific marker is available. We here investigated whether angptl4 mRNA 1) could be a useful diagnostic and/or prognostic marker of ccRCC in a large and comprehensive retrospective series, 2) induction is dependent on the VHL status of tumors.Methodology/Principal FindingsUsing in situ hybridization, we report that angptl4 mRNA is expressed in 100% of both sporadic (n = 102) and inherited (n = 6) primary ccRCCs, without any statistical association with nuclear grade (p = 0.39), tumor size (p = 0.09), stage grouping (p = 0.17), progression-free survival (p = 0.94), and overall survival (p = 0.80). Angptl4 mRNA was also expressed in 26 (87%) of 30 secondary ccRCCs but neither in any other secondary RCCs (n = 7). In contrast, angptl4 mRNA was neither expressed in 94% non-ccRCC renal tumors (papillary RCCs (n = 46), chromophobe RCCs (n = 28), and oncocytomas (n = 9)), nor in non-renal clear cell carcinomas (n = 39). Angptl4 expression was also examined in tumors associated (n = 23) or not associated (n = 66) with VHL disease. 40 (98%) hemangioblastomas expressed angptl4 whereas all pheochromocytomas (n = 23) and pancreatic tumors (n = 25) were angptl4-negative, whatever their VHL status.Conclusions/SignificanceAngptl4 mRNA expression was highly associated with ccRCC (p = 1.5 10−49, Chi square test) allowing to define its expression as a diagnosis marker for primary ccRCC. Moreover, angptl4 mRNA allows to discriminate the renal origin of metastases of clear-cell carcinomas arising from various organs. Finally, inactivation of VHL gene is neither necessary nor sufficient for angptl4 mRNA induction.

Emerging Roles of Angiopoietin-like 4 in Human Cancer

“…ANGPTL4 expression was observed to be elevated in numerous cancers at both the mRNA and protein level ( Table 2). Given the implications that ANGPTL4 may have on cancer progression, a recent report suggested that ANGPTL4 mRNA could be used as a diagnostic marker to distinguish primary and metastatic clear cell renal cell carcinoma (53). Several other studies have also delineated the ANGPTL4 expression level in primary and invasive tumors, showing that high ANGPTL4 mRNA and protein expression in human tumor biopsies often correlates with a poor prognosis and a poor disease outcome (25,33,34).…”

Alteration of Developmental and Pathological Retinal Angiogenesis in angptl4-deficient Mice

“…ANGPTL4 does not bind to TIE-2 and is still an orphan ligand. In humans, ANGPTL4 is expressed in ischemic cardiovascular pathologies and in tumors (9,12,13). Both in vitro and in vivo gain of function experiments showed that ANGPTL4 regulates context-dependent angiogenesis and vascular permeability (14 -16).…”

Molecular Characterization of Glioblastoma Cancer Stem Cells

“…ANGPTL4 has been identified as a prominent gene in in vivo hypoxia gene sets that predict poor outcome in multiple tumor types. In a study of several epithelial tumor types, ANGPTL4 levels increased as tumors progress from local to metastatic disease [107,108]. In our studies, we found a strong relationship between poor patient performance and survival and enhanced expression of STAT3 and ANGPTL4 in GBM patients.…”

“…While first identified for its involvement in lipid and glucose metabolism, a novel role for ANGPTL4 in cancer progression has emerged [106]. Notably, expression of ANGPTL4 has been identified in an in vivo hypoxia gene signature that predicts poor outcome in multiple tumor types [107,108]. Evidence suggests ANGPTL4 provides signals to support several tumorigenic activities characteristic of the metastatic cascade, such as cell proliferation, migration, survival, angiogenesis, epithelial-to-mesenchymal transition, and the maintenance of stem cell niches [109].…”