Inheritance of a defective copy of the von Hippel-Lindau (VHL) gene leads to the most common cause of inherited renal cell carcinoma (RCC). In addition, most patients with sporadic RCC have aberrant VHL. In the absence of VHL, hypoxia-inducible factor a accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. We review here the biology of RCC and how a combination of proximal and distal block of VHL/hypoxia-inducible factor a pathway by novel targeted agents, including sunitinib, sorafenib, bevacizumab, everolimus, and temsirolimus, has led to significant improvements in progression-free survival.

Metastatic renal cell carcinoma (RCC) has historically been refractory to cytotoxic and hormonal agents; only interleukin 2 and interferon alpha provide response in a minority of patients. We reviewed RCC biology and explored the ways in which this understanding led to development of novel, effective targeted therapies. Small molecule tyrosine kinase inhibitors, monoclonal antibodies and novel agents are all being studied, and phase II studies show promising activity of sunitinib, sorafenib and bevacizumab. The results of phase III studies will determine the role of these agents in metastatic RCC. British Journal of Cancer (2006) Malignant renal cell carcinoma (RCC) accounts for 2 -3% of cancer incidence and results in over 100 000 worldwide deaths annually. In developed nations the average age-adjusted incidence of RCC is approximately 12/100 000 in men and 5/100 000 in women. RCC is the most lethal urologic cancer and the sixth leading cause of cancer deaths in the developed nations. For reasons that are unclear, RCC age-adjusted incidence has been rising for the past 30 years within the US and most European nations at an annual rate of approximately 3% (Chow et al, 1999). For those who present with metastasis, the overall clinical course of RCC varies; approximately 50% of patients survive o1 year and 10% survive for over 5 years . For those who present with early stage disease, radical nephrectomy is the treatment of choice; however, 30% of these patients will relapse and develop future metastasis. Chemotherapy has consistently been an ineffective form of treatment for RCC (Motzer et al, 1996), and until recently, the only effective treatment for metastatic disease was cytokine-based immunotherapy with interferon (IFN)-a or interleukin (IL)-2, which have a response rate of approximately 15% (Rosenberg et al, 1987). Recent advances in understanding the biology and genetics of RCC have led to several novel targeted approaches for the treatment of metastatic RCC, with higher response rates.

The mechanism by which renal cell carcinoma (RCC) colonizes the lung microenvironment during metastasis remains largely unknown. To investigate this process, we grafted human RCC cells with varying lung metastatic potential in mice. Gene expression profiling of the mouse lung stromal compartment revealed a signature enriched for neutrophil-specific functions that was induced preferentially by poorly metastatic cells. Analysis of the gene expression signatures of tumor cell lines showed an inverse correlation between metastatic activity and the levels of a number of chemokines, including CXCL5 and IL8. Enforced depletion of CXCL5 and IL8 in these cell lines enabled us to establish a functional link between lung neutrophil infiltration, secretion of chemokines by cancer cells, and metastatic activity. We further show that human neutrophils display a higher cytotoxic activity against poorly metastatic cells compared to highly metastatic cells. Together, these results support a model in which neutrophils recruited to the lung by tumor-secreted chemokines build an antimetastatic barrier with loss of neutrophil chemokines in tumor cells acting as a critical rate-limiting step during lung metastatic seeding.

Male germ cell tumors (GCTs) are uniquely sensitive to cisplatin-based chemotherapy, with more than 90% of newly diagnosed cases cured. The underlying cause for resistance to treatment in 20 ± 30% of metastatic lesions remains to be identi®ed. Unlike other solid tumors, no mutations in the TP53 gene have been identi®ed to date in random panels of GCT specimens, which could account for the exquisite sensitivity of these tumors to genotoxic insult. However, in a panel of resistant GCTs that did either not respond to cisplatin-based chemotherapy or subsequently relapsed and resulted in the death of the patient, we have now identi®ed a subset of tumors to contain TP53 mutations within exons 6 ± 9. A cell line derived from one of these tumors (228A) displayed the same TP53 mutation as the tumor specimen, expressed only mutant TP53 mRNA, and exhibited a relative resistance to cisplatin in vitro in comparison to a cell line (218A) derived from a responsive tumor with wild-type TP53. The resistant cell line displayed a much reduced apoptotic cell death and did not exhibit an induction of transcription of the p53-responsive genes WAF1 and MDM2 following cisplatin treatment, compared to that observed in the sensitive cell line. The levels of bax, an agonist of apoptosis, were found to be reduced in the resistant cell line. The simplest explanation for the resistance of this subset of GCTs that are resistant to cisplatin-based chemotherapy, is the inability of the cells to mount an apoptotic response following exposure due to a functionally inactivating mutation in the TP53 gene.

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