The role of rechallenge with targeted therapies in metastatic renal-cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is the most common adult renal neoplasm and its incidence continues to increase. Collagen is the most abundant extracellular matrix protein in stroma, and contributes to the development and progression of ccRCC. We examined the human collagen type XXIII α1 chain (COL23A1) expression in ccRCC and the relationship between COL23A1 and patients’ survival. We found COL23A1 mRNA was elevated in tumor compared with adjacent normal tissues, which was further validated by TCGA cohort. IHC results from 151 ccRCC cases suggested that high COL23A1 expression correlated with larger tumor size (P = 0.017) and advanced T stage (P = 0.011). The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P = 0.002). In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P = 0.017). Furthermore, COL23A1 knockdown repressed proliferation of ccRCC cell lines by blocking cell cycle progression. Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1. Our data indicate that COL23A1 may be a novel prognostic indicator in ccRCC and might be a specific and accessible biomarker as well as a potential new target for clinical diagnosis of ccRCC.

Section: Introductionmentioning

confidence: 99%

The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma

Chang

et al. 2017

“…Several strategies have been developed to target angiogenesis for the treatment of mRCC, including inhibition of VEGF receptors (inhibition of tyrosine kinase activity) or VEGF protein binding33. Several additional kinase inhibitors, including sunitinib, are used for the treatment of mRCC34. However, the relationship between AR signaling and angiogenesis has not been systemically studied.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling

Guan

Fan

et al. 2016

Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression. The results obtained using an in vivo mouse model and a human clinical sample survey confirmed the role of AR in promoting RCC progression through enhancement of EC proliferation and/or recruitment via altered AKT → NF-κB → CXCL5 signaling. Targeting this newly identified AR-induced AKT → NF-κB → CXCL5 pathway may facilitate the development of new therapies for slowing RCC progression.

“…Approximately 30% of patients have metastases at first diagnosis, and another 20% of RCC patients with clinically localized disease will develop metastasis even after curative nephrectomy3. Although novel target therapies have been developed, most metastatic RCCs still eventually cause death4. Prediction models identifying patients with poor prognosis, who may benefit from early systematic therapy, are greatly needed.…”

mentioning

confidence: 99%

Prognostic and clinicopathological role of high Ki-67 expression in patients with renal cell carcinoma: a systematic review and meta-analysis

Xie

Chen

et al. 2017

Previous studies have elevated the prognostic value of Ki-67 in renal cell carcinoma (RCC), but the reports are controversial and inconsistent. We conducted a systematic review and meta-analysis to clarify the significance of Ki-67 in RCC prognosis. We systematically searched PubMed, Web of Science, and Embase to identify relevant studies until April 2016. Based on the inclusion and exclusion criteria, 20 studies, including 5,398 patients, were eligible for further analysis. Results showed that high Ki-67 expression in RCC was associated with poor OS (HR = 1.95, 95% CI: 1.44–2.64), CSS (HR = 1.67, 95% CI: 1.47–1.89), and DFS (HR = 2.56, 95% CI: 1.79–3.67). In addition, high Ki-67 expression was significantly associated with TNM stage (III/IV vs. I/II: RR = 2.03, 95% CI: 1.68–2.44), pathological T stage (T3/T4 vs. T1/T2: RR = 1.67, 95% CI: 1.35–2.06), metastasis (yes vs. no: RR = 2.15, 95% CI: 1.77–2.62), and Fuhrman grade (III/IV vs. I/II: RR = 1.77, 95% CI: 1.20–2.60). Our study suggested that Ki-67 was a prognostic marker in RCC. High Ki-67 expression was correlated with poor prognosis and advanced clinicopathological features, and it could serve as a biomarker for disease management.