Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits
Open Access
- 5 November 2020
- journal article
- research article
- Published by EMBO in EMBO Molecular Medicine
- Vol. 12 (12), e11889
- https://doi.org/10.15252/emmm.201911889
Abstract
An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address, this we developed an extensive series of 27 patient biopsy-derived orthotopic xenograft models (Ren-PDOX) that represent inter-patient heterogeneity. In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species-discriminative RNA sequencing identified a tumor cell-specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion-annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro-invasive subtype of Ren-PDOXs. Validation in an independent series of 15 antiangiogenic-treated patients confirmed that pre-treatment ALDH1A3 can significantly discriminate patients with pro-aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment.Funding Information
- Ministerio de Economía, Industria y Competitividad, Gobierno de España (SAF2016‐79347‐R)
- Associazione Italiana per la Ricerca sul Cancro (IG#14032)
This publication has 53 references indexed in Scilit:
- Rapid Angiogenesis Onset after Discontinuation of Sunitinib Treatment of Renal Cell Carcinoma PatientsClinical Cancer Research, 2012
- A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell CarcinomaScience Translational Medicine, 2012
- Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine TumorsCancer Discovery, 2012
- Incidence of brain metastases in renal cell carcinoma treated with sorafenibAnnals of Oncology, 2010
- Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell CarcinomaJournal of Clinical Oncology, 2009
- Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant MetastasisCancer Cell, 2009
- Bevacizumab Plus Interferon Alfa Compared With Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: CALGB 90206Journal of Clinical Oncology, 2008
- Modes of resistance to anti-angiogenic therapyNature Reviews Cancer, 2008
- Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trialThe Lancet, 2008
- Brain Metastases in Patients With Renal Cell Cancer Receiving New Targeted TreatmentJournal of Clinical Oncology, 2008