Biology of renal cell carcinoma (RCC)

The tumor biology of RCC includes a complex cascade of intracellular events, including the accumulation of HIF-1α within the cell. In RCCs, HIF-1α directly induces high expression of VEGF, one of the key mediators of tumor angiogenesis.^1,2

Cohen HT, McGovern FJ. N Engl J Med. 2005;353:2477-2490. Copyright © 2005 Massachusetts Medical Society.

Approximately 80% of renal cell carcinomas (RCCs) have clear-cell histology—that is, cells appear clear under a microscope.³ In the majority of clear-cell RCCs, the von Hippel-Lindau tumor suppressor gene (VHL) is inactivated through means such as deletion or other genetic mutation.⁴

Under normoxic conditions, the VHL protein (pVHL) closely regulates hypoxia-inducible factor-1α (HIF-1α) by causing its rapid degradation, so that HIF-1α is not normally found in the cell. As a result, HIF-1α is unavailable to bind to the corresponding subunit, HIF-1β, and the subsequent cascade of cellular signals does not occur.² In contrast, under hypoxic conditions, pVHL regulation of HIF-1α is impaired. As a result, HIF-1α is not degraded. The resulting accumulation of HIF-1α within the cell is responsible for the high degree of vascularity commonly seen in VHL-deficient tumors.² A critical consequence of VHL inactivation is upregulation of vascular endothelial growth factor (VEGF) via a pathway involving accumulation of HIF-1α.^1,2,5

Expression of pro-angiogenic factors under hypoxic conditions

 

This image is a simplified representation of HIF regulation under normoxic and hypoxic conditions. Under normoxic conditions (shown at right), HIF-1α is tagged for proteasome degradation in a process known as ubiquitination. However, under hypoxic conditions (shown at left), HIF-1α accumulates in the cell and is able to dimerize with HIF-1β. This interaction results in the upregulation of a number of pro-angiogenic factors, including VEGF.¹

George DJ, Kaelin WG Jr. N Engl J Med. 2003;349:419-421. Copyright © 2003 Massachusetts Medical Society.

Research also indicates that VHL silencing results in defects in a process called ubiquitination, in which cellular proteins (in this case, HIF-1α) are tagged for degradation with molecules known as ubiquitins.¹ Impairments in the ubiquitination pathway lead to the accumulation of HIF-1α within the cell, even without hypoxic conditions.² (For more information on ubiquitination, click here.)

HIF-1α is a key transcriptional factor in the molecular pathway of hypoxia and regulates the expression of a number of genes whose products are critical to tumor angiogenesis, proliferation, survival, and metabolism. With respect to angiogenesis in RCC, one of the most important gene products downstream of HIF-1α is VEGF.^2,4,5

References:

1.

George DJ, Kaelin WG Jr. N Engl J Med. 2003;349:419-421. PMID: 12890838

2.

Haase VH. Kidney Int. 2006;69:1302-1307. PMID: 16531988

3.

American Cancer Society. What is kidney cancer? http://www.cancer.org/Cancer/KidneyCancer/DetailedGuide/kidney-cancer-adult-what-is-kidney-cancer. Accessed August 13, 2010.

4.

Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. PMID: 15534359

5.

Iliopoulos O, Levy AP, Jiang C, Kaelin WG Jr, Goldberg MA. Proc Natl Acad Sci USA. 1996;93:10595-10599. PMID: 8855223