Sequential pathogenesis of metastatic VHL mutant clear cell renal cell carcinoma: Putting it together with a translational perspective

Niraj Shenoy, L. Pagliaro

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Clear cell renal cell carcinoma (ccRCC) accounts for ~80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ~75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.

Original languageEnglish (US)
Pages (from-to)1685-1695
Number of pages11
JournalAnnals of Oncology
Volume27
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Fingerprint

Renal Cell Carcinoma
Epigenomics
Immune Evasion
Pentose Phosphate Pathway
DNA Mismatch Repair
Epithelial-Mesenchymal Transition
Translational Medical Research
Germ-Line Mutation
Glycolysis
Drug Delivery Systems
Standard of Care
Tumor Suppressor Genes
Genes
Disease Progression
Molecular Biology
Cell Cycle
Genome
Neoplasm Metastasis
Therapeutics
Hypoxia

Keywords

  • Clear cell RCC
  • Epigenetics
  • HIF pathway
  • Molecular pathogenesis
  • Translational research
  • Von Hippel-Lindau

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Sequential pathogenesis of metastatic VHL mutant clear cell renal cell carcinoma : Putting it together with a translational perspective. / Shenoy, Niraj; Pagliaro, L.

In: Annals of Oncology, Vol. 27, No. 9, 01.09.2016, p. 1685-1695.

Research output: Contribution to journalArticle

@article{286dbc6fd91344f6ab215c9433103d50,
title = "Sequential pathogenesis of metastatic VHL mutant clear cell renal cell carcinoma: Putting it together with a translational perspective",
abstract = "Clear cell renal cell carcinoma (ccRCC) accounts for ~80{\%} of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ~75{\%} of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.",
keywords = "Clear cell RCC, Epigenetics, HIF pathway, Molecular pathogenesis, Translational research, Von Hippel-Lindau",
author = "Niraj Shenoy and L. Pagliaro",
year = "2016",
month = "9",
day = "1",
doi = "10.1093/annonc/mdw241",
language = "English (US)",
volume = "27",
pages = "1685--1695",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - Sequential pathogenesis of metastatic VHL mutant clear cell renal cell carcinoma

T2 - Putting it together with a translational perspective

AU - Shenoy, Niraj

AU - Pagliaro, L.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Clear cell renal cell carcinoma (ccRCC) accounts for ~80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ~75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.

AB - Clear cell renal cell carcinoma (ccRCC) accounts for ~80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ~75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.

KW - Clear cell RCC

KW - Epigenetics

KW - HIF pathway

KW - Molecular pathogenesis

KW - Translational research

KW - Von Hippel-Lindau

UR - http://www.scopus.com/inward/record.url?scp=84995678166&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995678166&partnerID=8YFLogxK

U2 - 10.1093/annonc/mdw241

DO - 10.1093/annonc/mdw241

M3 - Article

C2 - 27329246

AN - SCOPUS:84995678166

VL - 27

SP - 1685

EP - 1695

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 9

ER -