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REVIEW ARTICLE
Year : 2012  |  Volume : 2  |  Issue : 1  |  Page : 3-7

An overview of angiogenesis and renal cell carcinoma


1 Vinayaka Missons Sikkim College of Pharmaceutical Sciences, Vinayaka Missons Sikkim University, Tadong, East Sikkim, India
2 Central Council for Research in Ayurveda and Siddha, Ministry of Health and Family Welfare, Government of India, Institutional Area, Janakpuri, New Delhi, India

Date of Submission04-Aug-2011
Date of Acceptance29-Sep-2011
Date of Web Publication23-Feb-2012

Correspondence Address:
Yadu Nandan Dey
Central Council for Research in Ayurveda and Siddha, Ministry of Health and Family Welfare, Govt. of India, 61-65, Institutional Area, Janakpuri Opp. 'D' Block, New Delhi - 110 058
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.93123

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   Abstract 

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney, and the incidence is increasing very rapidly across all population groups. Accumulation of hypoxia-induced factors and the over-expression of vascular endothelial growth factor (VEGF) are the most important predisposing factors for the progression of the disease. Angiogenesis facilitates tumor growth progression by supplying adequate oxygen and nutrition to the tumor cells through a series of interrelated steps. VEGF, Placental Growth Factor (PIGF), and Basic Fibroblast Growth Factor (bFGF) work together to increase angiogenesis in RCC. This review focuses on the possible targets in the treatment of the disease. Our literature review covers the last 15 years of reaseach related to this topic. We conclude that targeted therapies for RCC should be directed against specific molecules and signaling pathways and the therapy should be more selective for better tolerance.

Keywords: Angiogenesis, placental growth factor, renal cell carcinoma, Von Hippel-Lindau gene, vascular endothelial growth factor


How to cite this article:
De S, Dey YN, Sarkar P, Gaidhani S. An overview of angiogenesis and renal cell carcinoma. Int J Nutr Pharmacol Neurol Dis 2012;2:3-7

How to cite this URL:
De S, Dey YN, Sarkar P, Gaidhani S. An overview of angiogenesis and renal cell carcinoma. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 Nov 17];2:3-7. Available from: http://www.ijnpnd.com/text.asp?2012/2/1/3/93123


   Introduction Top


Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. It is highly aggressive in nature and is the most lethal among the urologic malignancies. [1] RCC arises from the renal epithelium. About 85% of renal cancers are RCC. It accounts for approximately 95000 deaths per year and the mortality rate is steadily increasing at the rate of 2.5% per year across all population groups. [2],[3] Up to 30% of patients with RCC present with metastatic disease, and recurrence occurs in approximately 40% of patients after treatment of a localized tumor. [4],[5],[6] In children with RCC, up to 42.5% have general symptoms such as fever (22.5%), nausea/vomiting (17.5%), pallor (10%), malaise (10%), and weight loss (5%). High levels of serum lactate dehydrogenase, low hemoglobin level, and high corrected level of serum calcium are the prognostic markers for metastatic RCC. [7] The average survival of patients with advanced RCC is approximately 12 months. Up to a third of patients present with advanced disease, and a third of patients treated surgically with curative intent relapse with advanced disease. [8] Developments in the knowledge of molecular biology on RCC have identified angiogenesis as playing a key role in the pathophysiology of RCC. Von Hippel-Lindau (VHL) gene alterations, hypoxia-inducible factor-a (HIFa) accumulation, and vascular endothelial growth factor (VEGF) over-expressions are important mediators of this process. [9] Hereditary and sporadic RCCs are characterized by inactivation of the VHL gene, which causes hyperactivity of the HIFa and, as a result, production of angiogenic factors like VEGF and platelet-derived growth factor (PDGF). The activity of these factors is associated with oncogenesis, tumor growth, and increased metastatic potential of RCC. [10]

Plant-based medicines still play an important role in the primary healthcare of 80% of the world's population in both underdeveloped and developed countries. [11] The currently accepted 'modern medicine' or allopathy was gradually developed over the years by scientific observation. However, its basis remains rooted in traditional medicine and therapies. [12] The popularity of herbal medicines is due largely to their presumed safety, efficacy, cultural acceptability, and fewer side effects compared with prescription medications. [13] Several strategies have been developed to target angiogenesis for the treatment of metastatic RCC These include inhibition of VEGF receptors or VEGF protein, inhibition of binding to PDGF receptors, etc.


   Angiogenesis Top


Angiogenesis is the physiological process of the growth of new blood vessels from preexisting blood vessels. [14] Hypoxia-inducible factor (HIF) is a transcription factor that responds to reduced intracellular oxygen concentration. In the hypoxic condition, HIF accumulates in the cell and is transported to the nucleus where it induces the expression of a wide variety of target gene products such as growth factors, e.g., VEGF, fibroblast growth factor (FGF), and transforming growth factor (TGF), etc. These proteins in turn activate different signaling pathways, including PLCγ, PI3K, Smad, Src, etc., so that endothelial cell proliferation, vascular permeability and, ultimately, cell migration are increased. Extracellular matrix proteases induce tissue matrix remodeling and new tube formation occurs with the participation of the migrated endothelial cells. Various cytokines play key roles in the process. In addition to hypoxia, the PI3K and Ras pathways can also increase HIF expression by increasing HIF translation. [15] The growth of any tumor and its metastasis depend on the development of neovasculature in and around the tumor. [16] Angiogenesis facilitates tumor growth progression by supplying adequate oxygen and nutrition to the tumor cells through several interrelated steps. The mechanism regulating angiogenesis is tissue specific. [17] Angiogenic phenotype is regulated by the differential expression of growth factors and cytokines within the microenvironment of the organ. [18]


   Renal Cell Carcinoma and Angiogenesis Top


RCC is one of the most vascular of the solid tumors, which suggests a prominent role for angiogenesis in the pathogenesis of RCC. [19] It has been found that in four out of six patients, bFGF mRNA expression in RCC tissues is two- or three-fold higher than in surrounding normal cells. Thus, it appears that bFGF is one of the most important factors for angiogenesis in RCC. [20] The other two families of angiogenic factors are PIGF and VEGF, both structurally related to PDGF. VEGF is also known as vascular permeability factor and stimulates endothelial cell proliferation in vitro and has got in vivo angiogenic activity as well. [21],[22] The second secreted angiogenic factor with a role in angiogenesis in RCC is PIGF, which was first isolated from human placenta and choriocarcinoma cells. [23] In one study it has been found that the VEGF mRNA levels in the carcinoma tissues were significantly higher than that in adjacent normal tissues in 26 of 27 (96%) hypervascular RCCs, including small-sized tumors. This suggests that elevated VEGF expression is involved in the hypervascularity of RCC and plays an important role in determining the size, stage, and grade of carcinoma. VEGF, PIGF, and bFGF work together to increase angiogenesis in RCC and thus they can be used as tumor markers, especially in the early stage of the disease. [24]


   Molecular-Targeted Therapy for Renal Cell Carcinoma Top


Currently, many novel molecular targeted therapeutic agents are under preclinical and clinical trials. These targeted agents include tyrosine kinase inhibitors (TKI), small molecules, human monoclonal antibodies, etc. Many of them have shown antitumor activity in randomized clinical trials. [25]

Targeted therapies in practice

Vascular endothelial growth factor receptor tyrosine kinase inhibitors


Sunitinib : The expression of both PDGF and VEGF receptors is upregulated in clear-cell RCC and it was therefore logical to use sunitinib as a potential therapeutic agent in this disease as it can inhibit VEGFR-1, 2, and 3, as well as PDGFR-B and related RTIs. Preclinical studies showed selective in vivo inhibition of phosphorylation of VEGFR-2 and PDGF-b receptors, as well as in vitro inhibition of proliferation of endothelial cell and fibroblasts. The antitumor effect of sunitinib in mice has already been proved. [26],[27]

Sorafenib: Sorafenib is a potent inhibitor of RAF- 1, a key enzyme affecting the mitogen-activated protein kinase (MAPK) signaling pathway leading to cell proliferation. [28] However, sorafenib also has potent activity against VEGFR2, VEGFR3, PDGFB, Flt-3, and c-kit [29] and so can significantly inhibit neovascularization. [30]

Mammalian target of rapamycin inhibitors

Temsirolimus : This rapamycin derivative forms a complex with FK-506 binding protein-12 and, as a result, mammalian target of rapamycin (mTOR) activity (mTOR-raptor complex) is inhibited. [31]

Everolimus: This is an orally active mTOR inhibitor that inhibits the stress response signals in cancer via the PI3K-AKT pathway; this inhibits downstream signal transduction and prevents the signaling involved in the proliferation and survival of tumor cells. The mTOR kinase also controls the angiogenic pathway through the HIF1α and VEGF pathways.[32]

Monoclonal antibodies in renal cell cancer

Bevacizumab : This is a recombinant monoclonal VEGF antibody that binds and neutralizes circulating VEGF. [33]

Drugs under development

Other anti-angiogenic drugs are in different phases of clinical trials and many are showing promising results. Some of them are discussed here. Cetuximab, the chimeric monoclonal antibody is highly selective for the EGFR. It induces a broad range of cellular responses in tumors expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. [34],[35] The EGFR antibody produced a fairly satisfactory result in a trial conducted on 55 patients. [36] Pazopanib inhibits tyrosine kinase of VEGFR1-3, Platelet Derived Growth Factor Receptor (PDGFR) alpha and beta, and c-kit. It has been approved for use in RCC by the US Food and Drug Administration (FDA). [37] Volociximab, the IgG4 chimeric (82% human, 18% murine) monoclonal antibody (mAb) specifically binds to α5β1 integrin, which plays a specific role in cell proliferation, apoptosis, angiogenesis, and tumor metastasis. [38],[39] A preclinical model of choroidal neovascularization in cynomolgus monkeys showed that volociximab was a potent angiogenesis inhibitor. [40] A pharmacokinetic study showed that it can be safely administered at a dose of 15 mg/kg i.v. per week without causing severe toxicities. [41] BAY 73-4506 is an orally active drug targeting both tumor cell proliferation and vascularization through inhibition of receptors of tyrosine kinases (VEGFR, FGFR, PDGFR) and serine/threonine kinases (RAF and p38MAPK). Promising antitumor activity and good tolerability of BAY 73-4506 in patients with RCC was found in a phase II study. [42] Cediranib is an oral active and highly potent VEGFR TKI. A phase II study on 43 patients has shown substantial antitumor activity, with 84% tumor control rates in patients with previously untreated advanced RCC. [43] Tivozanib is able to markedly inhibit ligand-induced phosphorylation of VEGFR-1, VEGFR-2, and VEGFR-3 at picomolar concentrations. In preclinical studies, significant inhibition of tumor growth and angiogenesis was found in several different xenograft tumor models in athymic rats. Results from a phase II clinical trial on advanced RCC patients reported an overall response rate of 25.4% and a median progression-free survival of 11.8 months for patients treated with tivozanib as a single agent. [44] Besides these drugs, many others of different groups are under study, e.g., VEGFR-TKIs like telatinib, brivanib, motesani, XL880, XL820, recentin, OSI-930, CEP-11981, and CHIR-258; integrin inhibitors like vitaxin (MEDI-522), cilengitide (EMD 121974), and E7820; and c-MET inhibitors like AMG 102, ARQ-197, MP-470, and PF2341066. [45]


   Risk of Intracranial Bleeding During Anti-Vascular Endothelial Growth Factor Therapy Top


Anti-VEGF therapy with the monoclonal antibody bevacizumab and the TKIs sorafenib and sunitinib has demonstrated clinical benefit in randomized clinical trials involving patients with a number of solid tumor types and has already been approved by the FDA. Many clinical studies report that there is an increased bleeding risk with bevacizumab therapy, which may be due to alterations in endothelial function. Localized tumor necrosis, in association with diminished regeneration of endothelial cells and increased vascular fragility due to VEGF blockade, may be involved in the pathogenesis. One study reported that hematemesis or hemoptysis occurred in 10% of patients treated with bevacizumab in combination with carboplatin and paclitaxel. [46],[47],[48],[49] CNS metastases are common (17%) in renal carcinomas. [50] Autopsy series indicate the presence of brain metastases in 25% of cases. [51] All phase I, II, and III studies on anti-VEGF therapy report an increased incidence of hemorrhage and increased risk of bleeding in patients with cerebral metastases or high-grade gliomas. [52]


   Conclusion Top


In cases of hereditary and sporadic RCC the VHL gene plays a very important role, causing hyperactivity of the HIFa; as a result, over-production of VEGF and PDGF-like angiogenic factors occur. Overactivity of these factors are associated with oncogenesis, tumor growth, and increased metastatic potential of RCC. Many prognostic factors involving the anatomical, histological, and clinical aspects of the disease have been identified and, accordingly, several strategies have been developed to target angiogenesis for the treatment of metastatic RCC. Approaches include inhibition of VEGF receptors or inhibition of binding to the VEGF protein; PDGF-receptor inhibitors are also being targeted. Several drugs have been already been marketed and clinical trials of many promising compounds are on the verge of completion. We are expecting encouraging results. Unfortunately, however, targeted therapies are not a permanent solution for all patients. Targeted therapies should be directed against molecules and signaling pathways that are specific to tumor growth. These therapies should be more selective in their effects than chemotherapy, which will ensure that they are better tolerated.


   Acknowledgment Top


We would like to thanks the Chairman, Pro-Chancellor, Vice-Chancellor, and Director Administration of Vinayaka Missons Sikkim University, Tadong - 737102, East Sikkim, India, for their kind support.

 
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