Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1alpha in clear cell renal carcinomas.

Wiesener MS, Münchenhagen PM, Berger I, Morgan NV, Roigas J, Schwiertz A, Jürgensen JS, Gruber G, Maxwell PH, Löning SA, Frei U, Maher ER, Gröne HJ, Eckardt KU.

Department of Nephrology and Medical Intensive Care, Charité, Humboldt University, 13353 Berlin, Germany.

Cancer Res. 2001 Jul 1;61(13):5215-22.

4/9/2009

Renal cell carcinoma• 54,000 new cases of kidney cancer in 2008 and ~13,000 deaths

– Among the 10 most common types of cancer• Treatment

– Nephrectomy--surgical removal – Cryotherapy and/or radiation; poor response to chemotherapy– Several tyrosine kinase and mTOR inhibitors – Immunotherapy--IL-2 and interferon-

www.cancer.org

• Clear cell RCC

– Most common form (8/10)

– Worst prognosis

– VHL inactivation plays a causal role in hereditary and sporadic ccRCC

• Non-clear cell RCC

– Papillary, chromophobe, and collecting duct RCC

ccRCC

von Hippel-Lindau • E3 ubiquitin ligase

– Targets proteins for proteasomal degradation domain is substrate-docking interface– Recognizes hydroxylated proline

• Tumor suppressor– Reintroduction into RCC cells suppresses tumor formation in xenograft

and restores HIF hypoxic induction• von Hippel-Lindau disease

– Haemangioblastomas and tumors of the kidney, adrenal glands, pancreas

Kaelin WG Nat Rev Cancer (2008)

Hypoxia-inducible factor (HIF)

• Transcription factor (O2 sensitive) and (constitutive)

subunits– Gene targets include VEGF, GLUT-

1/3, erythropoietin, and MMPs– At least 3 family members (HIF1-3)

• Normoxia– Prolines are hydroxylated causing

recognition by VHL and subsequent degradation

Bertout JA. Nat Rev Cancer (2008)

• Hypoxia

– Lack of O2 leads to reduced hydroxylation and stabilization of HIF

• HIF staining is often seen at the interface between necrotic and tumor tissue or a the invasive tumor front– What about tumors formed due to genetic predisposition to HIF

deregulation?

Copyright ©2001 American Association for Cancer Research

Fig. 1

Copyright ©2001 American Association for Cancer Research

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Copyright ©2001 American Association for Cancer Research

Fig. 3

Copyright ©2001 American Association for Cancer Research

Fig. 4

Copyright ©2001 American Association for Cancer Research

Fig. 5

General conclusions

• HIF-1 is overexpression leads to homogenous staining– Low HIF-1 ccRCCs and non-ccRCCs had focal

staining

• Mutations in VHL gene only found in subset of ccRCCs that overexpressed HIF-1 – ~57% (doesn’t include gene silencing)

• Correlation between HIF-1 and expression of VEGF and GLUT1