Faculty of Pharmacy Biochemistry Department
Biochemical Changes on Renal Cell Carcinoma
PB401n
Contents Definition ............................................................................................................................... 3 Pathophysiology .................................................................................................................... 4 Epidemiology ........................................................................................................................ 5 Symptoms .............................................................................................................................. 5 Risk factors ............................................................................................................................ 6 Cigarette smoking .............................................................................................................. 6 Hypertension ...................................................................................................................... 6 Obesity ............................................................................................................................... 6 Alcohol consumption and Diet .......................................................................................... 6 Others ................................................................................................................................ 6 Biomarkers of RCC ............................................................................................................... 7 Diagnosis ............................................................................................................................... 7 Treatment ............................................................................................................................... 8 References ........................................................................................................................... 10
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RENAL CELL CARCINOMA Definition Renal Cell Carcinoma (abbreviated as RCC.) is a wide different group of malignant tumors that develop within the epithelial tissues of the kidney and varies in morphological and histological features. They were previously known as Hypernephoroma and Grawitz Tumours (Schwab, 2008) (Tannir, 2014). According the latest classification of WHO (2004), RCC is classified into the following types •
Clear-Cell Renal Cell Carcinoma (ccRCC); it is the most known type with a prevalence percentage of 70% approximately of all RCCs.
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Papillary Renal Cell Carcinoma (PRCC); it is also known as ‘Chromophil’. PRCC is the second most common type with a prevalence percentage of 15% approximately of all RCCs.
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Chromophobe Renal Cell Carcinoma (ChRCC); despite having prevalence of 5% approximately, it is third most common type.
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Others less commonly occur types includes; Collecting Ducts Carcinoma, Mucinous Tubular and Spindle Cell Carcinoma, RCC associated with Xp11.2 Chromosome Translocation and Unclassified RCC category (Bukowski and Novick, 2000).
Figure I Represents histological differences between subtypes or RCC
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Pathophysiology The RCC genesis lies mainly through a pathway starting from inactivation of tumor suppressor gene named ‘von Hippel-Lindau’ (VHL). VHL gene that resides on chromosome 3 is responsible for transcription of pVHL protein which has an oxygen sensor effect that is essential for degradation process regulation of a transcription factor ‘Hypoxia-InducibleFactor’ (HIF). HIF is responsible for activation of some genes that are responsible for activation of adapting mechanism of the cell to hypoxia by binding to hypoxia-related elements (HREs). One of these important targets is the ‘vascular endothelial growth factor’ (VEGF) which is responsible for the formation of blood supplying capillaries to the RCC in a process named after Angiogenesis. Consequently, (mTOR) pathway is over-stimulated leading to RCC initiation (Tannir, 2014).
Figure II Represents effect of pVHL, HIF on Hypoxia effect and the consequent VEGF stimulation and final tumorigenesis effect.
The second known way of RCC pathogenesis is believed to be sporadic and, also, based on inactivation of VHL gene in one of the following ways; VHL somatic mutation, hypermethylation that causes diallelic deactivation, or heterozygosity loss in the gene locus (Tannir, 2014).
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Epidemiology RCC possibility to affect male is twice as affecting females. Also, it was noticed that the prevalence of RCC increases with increasing age, specially, in sixties and seventies. Moreover, it was recorded that the mortality rate of the RCC has passed 60%, lately. However, it was also noted that incidence rate has been increasing with a lower rate over the past 10 years. In addition, 98% of adult RCC are of sporadic origin and it seems reasonable as von Hippel-Lindau familial cancer syndrome (a syndrome where VHL gene is mutated or absent and it is responsible for hereditary pathogenesis) occurs only to 0.003% of newborns (Cassidy, Bissett and Spence-Obe, 2002).
Figure III represents mortality rate percentage against staging Figure IV represents prevalence based on gender and age
Furthermore, there are more than 140 thousand people develops RCC, yearly (Schwab, 2008).
Symptoms Surprisingly, renal cell carcinoma is asymptomatic for most of the patients in early stages. However, in late stages, local pain that may originate in lungs, bone or lymph node due to metastasis invasion. The most recorded symptoms were as follows; hematuria, flank pain, palpable mass, weight loss, anemia and hypertension. There are other symptoms but were less incident such as pyrexia, polycythemia, hypercalcemia and paraneoplastic syndromes (Cassidy, Bissett and Spence-Obe, 2002).
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Risk factors Cigarette smoking The most linked risk factor to RCC is cigarette smoking as it was recorded that it increases the risk of RCC to male by 50% and to females by 20%. Hopefully, according to the same study, it was found that smoking cessation for more than 10 years decreases RCC risk by an average 23%. It is proposed that cigarette smoking increases oxidative stress and tissue hypoxia which is caused by CO (carbonmonoxide) (Cassidy, Bissett and Spence-Obe, 2002) (Tannir, 2014). Hypertension Also, hypertension has been confirmed by more than 15 studies that it increases susceptibility to RCC by 1.6 folds. But, the exact factual mechanism is not yet clear. However, it is assumed that hypertension-induced chronic renal hypoxia may result in renal injury that may lead to RCC (Chow, Dong and Devesa, 2010) (Tannir, 2014). Obesity In a meta-analysis, it was supposed that each increase in body mass index (BMI) by 5 units is related directly to up to 35% higher risk of RCC incidence in both genders (Tannir, 2014). Alcohol consumption and Diet Intake of baked and fried foods rich in carbohydrates was reported to increase RCC risk by more than 50% due to dietary acrylamide concentration in this kind of food. Surprisingly, alcohol consumption was recorded as RCC risk reducer as it reduces risk to RCC by more than 25% in people who consume around two cups of alcohol per day (Tannir, 2014). Others Finally, there were other medical conditions reported as risk factors for RCC but they are still need further investigations such as type II DM, long term hemodialysis, aspirin consumption and statins (Tannir, 2014).
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Biomarkers of RCC Based on the evidences reported by Bukowski and Novick in (2000), Cassidy, Bissett and Spence-Obe in (2002) & Schwab in (2008), all are confirmed of absence of specific biomarker for RCC. However, according to Tannir (2014), he describes in his book an evidence of de novo for RCC risk and early detection as well. He mentioned that according to two recent studies compared with controls, it was found that circulating microRNAs (abbreviated
as
miRNAs)
are
magnificently stable in cell-free form as they are protected from endogenous RNases. Thus, they are considered as promising biomarkers for RCC risk, diagnosis and prognosis. Also, in a review article by Pastore et al. Figure V indicates miRNA types involved in RCC pathogeneis as biomarkers
(2015), concluded inexistense of biomarker
for kidney cancer diagnosis but diagnostic adjuncts and prognostic indicators, yet, they didn’t mention miRNAs at all.
Diagnosis Diagnosis of RCC is primarily based on microscopic and macroscopic feature of the disease. Also, imaging tests are done such as CT scan & Chest x-ray which are very helpful in not only diagnosing but staging of RCC. The staging is done through the conventional TNM system. However, tumor Figure VI Represents CT Scan of RCC
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biopsy is considered the best way to determine absence or presence of malignancy (Petejove and Martinek, 2016).
Figure VII Represents staging of RCC
Treatment Treatment of RCC is based on its staging by dealing with approaches either confirmed localized RCC or metastatic one. Nephrectomy is the best way to treat localized ones based on life outcome qualities and oncological factors. Sometimes nephrectomy is followed by radiotherapy to insure remission (Petejove and Martinek, 2016).
Figure VIII Represents Nephrectomy
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However, metastatic tumors are more difficult to treat due to histological changes of different subtypes. Accordingly, several pharmacotherapeutic agents are used for systemic therapy with different mechanisms such as 5-fluorouracil (inhibition of DNA replication), Bevacizumab (VEGF inhibition), Interleukin 2 (stimulator for T-cell, tumor-specific CTLs, NK cells proliferation and then kills the cancer cells itself), Temsirolimus (mTOR inhibitor) and Sorafenib (VEGF and growth factors inhibitor) (Petejove and Martinek, 2016).
Figure IX represents mechanism of action of some pharmacotherapeutic agents
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References •
Bukowski, R. and Novick, A. (2000) Renal Cell Carcinoma: Molecular Biology, Immunology, New Jersey: Humana Press Inc.
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Cassidy, J., Bissett, D. and Spence-Obe, R. (2002) Oxford Handbook of Oncology, Newyork: Oxford University Press.
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Chow, W.-H., Dong, L. and Devesa, S. (2010) 'Epidemiology and risk factors for kidney cancer', Nature Reviews Urology, vol. 7, no. 5, May, pp. 245-257.
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Pastore, A.L., Palleschi, G., Silvestri, L. and Moschese, D. (2015) 'Serum and Urine Biomarkers for Human Renal Cell Carcinoma', Disease Markers, March.
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Petejove, N. and Martinek, A. (2016) 'Renal cell carcinoma: Review of etiology, pathophysiology and risk factors', Biomedical Papers of the Medical Faculty of the University Palacky, vol. 160, no. 2, June, pp. 183-194.
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Schwab, M. (2008) Encyclopedia of Cancer, 2nd edition, Springer-Verlag.
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Tannir, N.M. (2014) Renal Cell Carcinoma, New York: Oxford University Press.
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