Pathophysiology In as easy a way as I can describe it for you, the pathophysiology of a generic cancer cell is as follows.

The division, reproduction and replacement of all normal cells are controlled by regulator genes. A normal cell has regulator genes that produce hormones that act as on and off switches that begin or stop cell division and differentiation. A cell becomes cancerous when these regulator genes and the hormones they produce develop errors in function or stop functioning altogether. The normal cell then loses the ability to reproduce normally. The problem may be with the gene itself or in the synthesis of the hormones controlling this cell cycling process. What happens is that with the mechanism controlling their division and differentiation on the fritz these cells go into overdrive and begin unrestricted division and reproduction. Their rate of reproduction increases dramatically and in a very disorderly way compared to the normal cells around them. If they also lose their ability to differentiate a state called anaplasia results. As these cells continue to multiply they begin to lose some of their resemblance to the original cell they started from. This mutation continues if the process cannot be successfully stopped. The normal cells around them will try to "rescue" the situation by evoking the immune or inflammatory response and by releasing other growth factors, hormones and chemicals into the area in an attempt to stop what is going on. For one of these wayward cells to develop into a tumor, the body's immune system must fail to recognize or respond to it. In addition, there must be enough of a blood supply to bring oxygen and nutrients to nourish these mutated cells so they can thrive. Blood supply is a big factor in the early survival success of a tumor. However, once a tumor is able to successfully thrive and grow relentlessly, it will begin to produce it's own angiogenesis factors which will stimulate the formation of new blood vessels around them in order to meet its growth and nutrition demands. When tumor tissue extends close to or into blood or lymph circulation, cells will break off and travel to other sites in the body resulting in metastasis.

You'll want to review the normal cell cycle from anatomy and physiology and how cell are "turned on" or "off" to divide and reproduce themselves. The process is called social control and is regulated by social control genes with specific names. The tissue of origin for renal cell carcinoma (RCC) is the proximal renal tubular epithelium. Renal cancer occurs in a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET).

At least 4 hereditary syndromes associated with renal cell carcinoma are recognized: von HippelLindau (VHL) syndrome, hereditary papillary renal carcinoma (HPRC), familial renal oncocytoma (FRO) associated with Birt-Hogg-Dube syndrome (BHDS), and hereditary renal carcinoma (HRC).

von Hippel-Lindau syndrome von Hippel-Lindau disease is an autosomal dominant syndrome that confers predisposition to a variety of neoplasms, including the following:

Renal cell carcinoma with clear cell histologic features Pheochromocytoma Pancreatic cysts and islet cell tumors Retinal angiomas Central nervous system (CNS) hemangioblastomas Endolymphatic sac tumors Epididymal cystadenomas Renal cell carcinoma develops in nearly 40% of patients with von Hippel-Lindau disease and is a major cause of death among these patients. Deletions of 3p occur commonly in renal cell carcinoma associated with von Hippel-Lindau disease. The VHL gene is mutated in a high percentage of tumors and cell lines from patients with sporadic (nonhereditary) clear cell renal carcinoma. Several kindreds with familial clear cell carcinoma have a constitutional balanced translocation between 3p and either chromosome 6 or chromosome 8. Mutations of the VHL gene result in the accumulation of hypoxia inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor (VEGF) and its receptor (VEGFR). VEGF and VEGFR are important new therapeutic targets.

Hereditary papillary renal carcinoma Hereditary papillary renal carcinoma is an inherited disorder with an autosomal dominant inheritance pattern; affected individuals develop bilateral, multifocal papillary renal carcinoma. Germline mutations in the tyrosine kinase domain of the MET gene have been identified.

Familial renal oncocytoma and Birt-Hogg-Dube syndrome Individuals affected with familial renal oncocytoma can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney. Birt-Hogg-Dube syndrome is a hereditary cutaneous syndrome. Patients with Birt-Hogg-Dube syndrome have a dominantly inherited predisposition to develop benign

tumors of the hair follicle (ie, fibrofolliculomas), predominantly on the face, neck, and upper trunk, and these individuals are at risk of developing renal tumors, colonic polyps or tumors, and pulmonary cysts.

Hereditary renal carcinoma Affected individuals with this inherited medical condition have an increased tendency to develop oncocytomas, benign kidney tumors that have a low malignant potential.

A number of environmental and genetic factors have been studied as possible causes for renal cell carcinoma (RCC), such as the following:

Cigarette smoking doubles the risk of renal cell carcinoma and contributes to as many as one third of all cases. The risk appears to increase with the amount of cigarette smoking in a dose-dependent fashion. Obesity is another risk factor, particularly in women; increasing body weight has a linear relationship with increasing risk. Hypertension may be associated with an increased incidence of renal cell carcinoma. Phenacetin-containing analgesia taken in large amounts may be associated with increased incidence of renal cell carcinoma. In patients undergoing long-term renal dialysis, there is an increased incidence of acquired cystic disease of the kidney, which predisposes to renal cell cancer. Tuberous sclerosis appears to be associated with renal cell carcinoma, although the exact nature of this is unclear. In renal transplant recipients, acquired renal cystic disease of the native kidney also predisposes to renal cell cancer. Von Hippel-Lindau disease is an inherited disease associated with renal cell carcinoma. A prospective evaluation by Cho et al concluded that longer duration of use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for renal cell cancer.[4] Previous Next Sec Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. This disease is characterized by a lack of early warning signs, diverse clinical manifestations, and resistance to radiation and chemotherapy.[1, 2, 3]

Increasingly, renal cell cancers are diagnosed at an earlier stage, and nephron-sparing surgery and thermal ablation are gaining acceptance as a treatment of choice for smaller tumors. Radical nephrectomy is the standard for larger and central tumors.

In recent years, clinical trials have established the role of targeted therapy as the first line of therapy in patients with metastatic disease. Although the optimal treatment strategy continues to evolve, 3 agents that target angiogenesis (sunitinib, bevacizumab, and pazopanib) and a mammalian target of rapamycin (mTOR)targeted therapy (temsirolimus) have been approved as front-line agents. These agents have largely replaced cytokines (immunotherapy) in treatment-naive patients. Newer clinical trials are testing newer agents, combinations of approved agents, and the optimal sequencing of these agents.

Helpful? Here's some links to information on it. Get hunkered in for some serious reading. Some of this stuff is DEEP.