The adjuvant treatment of kidney cancer: a multidisciplinary outlook

Porta, Camillo; Cosmai, Laura; Leibovich, Bradley C.; Powles, Thomas; Gallieni, Maurizio; Bex, Axel

doi:10.1038/s41581-019-0131-x

Cited by 73 publications

(54 citation statements)

References 67 publications

(51 reference statements)

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“…Intriguingly, TOC significantly increased the TTP for dogs suffering from SBA, LA, and RCC, and some advanced types of adenocarcinomas that had higher mitotic index, invasive characteristics, and lymph node metastases. Several studies have reported that postoperative adjuvant treatment with sunitinib and sorafenib was efficacious in human patients with advanced RCC 22‐24 . Reports in the veterinary literature also have indicated that postoperative adjuvant treatment may improve survival time in dogs with SBA 25 .…”

Section: Discussionmentioning

confidence: 99%

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Yamazaki

Tanaka

Mie

et al. 2020

Veterinary Internal Medicne

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Background: Toceranib phosphate (TOC) could be made widely available for treating tumors in dogs if evidence shows that TOC inhibits recurrence after surgery.Objectives: To investigate how postoperative adjuvant treatment with TOC modulates the tumor microenvironment (TME), by assessing effects on angiogenic activity, tumorinfiltrating regulatory T cells (Tregs), and intratumoral hypoxia.Animals: Ninety-two client-owned dogs were included: 28 with apocrine gland anal sac adenocarcinoma, 24 with small intestinal adenocarcinoma, 22 with lung adenocarcinoma, and 18 with renal cell carcinoma.Methods: Retrospective, multicenter study comparing time to progression (TTP) between 42 dogs treated by surgery and TOC and 50 dogs treated by surgery alone.Differences were analyzed in the expression of vascular endothelial growth factor receptor-2 (VEGFR2) and the number of Foxp3 + Tregs and hypoxia-inducible factor (HIF)-1α + cells in tumor tissues sampled at the first and second (recurrence) surgeries.Results: Median TTP for dogs treated by surgery and TOC (360 days) was higher than that for dogs treated by surgery alone (298 days; hazard ratio, 0.82; 95% confidence interval [CI], 0.65-0.96; P = .02). In dogs treated by surgery and TOC, VEGFR2 expression and the number of Tregs and HIF-1α + cells were significantly lower in tissues sampled at the second surgery than in those sampled after the first surgery. In dogs treated by surgery alone, significant differences were found between samples from the 2 surgeries.Conclusions and Clinical Importance: Toceranib phosphate could prove to be a useful postoperative adjuvant treatment because of its modulation of the TME. K E Y W O R D S adenocarcinoma, postoperative adjuvant treatment, toceranib phosphate, tumor microenvironment

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Section: Discussionmentioning

confidence: 99%

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Yamazaki

Tanaka

Mie

et al. 2020

Veterinary Internal Medicne

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“…More than 10 histological and molecular subtypes of RCC have been identified, among which clear cell RCC (ccRCC) is the most common type and accounting for 80% of all cases 2 , 4 . The prognosis of RCC is poor because approximately 25% of patients present with metastases at the time of diagnosis, and another 30-35% of patients underwent resection for localized or locally invasive kidney cancer will develop potentially fatal metachronous distant metastases 5 , 6 . Therefore, a comprehensive understanding of RCC metastasis is urgently needed to develop effective targeted therapies for reducing the risk of recurrence and death from metastatic disease.…”

Section: Introductionmentioning

confidence: 99%

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma

Min¹,

Zhang²,

Li³

et al. 2020

Theranostics

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Background: Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. Methods: HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. Results: RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Conclusion: Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis.

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“…RCC is the malignant tumor with the highest mortality rate in the urogenital system. Over the past decade, there has been some progress in the treatment of RCC, such as the advent of targeted agents and immune checkpoint inhibitors [ 27 ]; however, the clinical outcomes of patients with RCC are still unsatisfactory [ 28 , 29 ]. Hence, it is necessary to identify new biomarkers that provide valuable information for clinicians to choose appropriate treatment options and predict prognosis of patients.…”

Section: Discussionmentioning

confidence: 99%

Chromodomain Helicase DNA-Binding Protein 5 Inhibits Renal Cell Carcinoma Tumorigenesis by Activation of the p53 and RB Pathways

Huang

Yan

Xiong

et al. 2020

BioMed Research International

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Chromodomain helicase DNA-binding protein 5 (CHD5) plays a crucial tumor suppressor role in multiple types of tumors. For this study, we investigated its clinical significance and the molecular mechanism(s) underlying tumorigenesis in renal cell carcinoma (RCC). Initially, CHD5 expression was assessed in primary tumor tissue and in tissue array. Correlations among CHD5 expression and clinicopathological characteristics were analyzed. Next, lentivirus-mediated CHD5 overexpression in the ACHN and 769-P cells was used to assess effects on proliferation, migration, invasion ability, and the regulation of the p14ARF/p53 and p16INK4a/RB signaling pathways. Finally, a xenograft mouse model was used to verify its impact on tumor growth in vivo. Results demonstrated that CHD5 was downregulated in tumor tissues and that low CHD5 expression was correlated with advanced TNM stage, high Fuhrman grade, lymph node metastasis, and poor survival. Overexpression of CHD5 inhibited proliferation, migration, and invasion in vitro; prompted cell cycle G1 phase arrest; induced apoptosis; and suppressed tumor growth in vivo. Furthermore, we confirmed that CHD5 activates the p53 and RB pathways to inhibit tumorigenesis in RCC. In summary, CHD5 is involved in the initiation and progression of RCC and may serve as a diagnostic biomarker and a potential therapeutic target for RCC.

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The adjuvant treatment of kidney cancer: a multidisciplinary outlook

Cited by 73 publications

References 67 publications

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

HSPA12A unstabilizes CD147 to inhibit lactate export and migration in human renal cell carcinoma

Chromodomain Helicase DNA-Binding Protein 5 Inhibits Renal Cell Carcinoma Tumorigenesis by Activation of the p53 and RB Pathways

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