**2. Signaling pathways in renal tumors**

Renal tumors originates from the tubular structures of the kidney and is calssified into four major histological cell types. Clear-cell renal tumor is the most common type, accounting for approximately 75% of all renal tumors. Other types are followed by papillary renal tumor (approximately 15%), chromophobe renal tumor (approximately 5%), and renal oncocytoma (approximately 5%) [7].

**2.3. HGF/MET pathway**

and metastasis [12].

**3.1. Prognostic model**

Changes in expression and activity of hepatocyte growth factor (HGF) and its receptor c-MET have been associated with renal tumors. HGF binding to MET leads to phosphory‐ lation of two tyrosine residues at the C-terminus of MET, which leads to the recruitment of adapter proteins and activation of PI3K/AKT pathway to promote renal tumor growth

Signaling Pathways and Biomarkers in Renal Tumors

http://dx.doi.org/10.5772/53787

33

In the cytokine era, Motzer et al. [13] reported Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification, which is based on data from 463 patients with advanced renal tumor who were treated with IFN-α cytokine therapy as first-line systemic therapy. The MSKCC risk classification extracted five variable risk factors for short survival: low Karnof‐ sky performance status (PS) (< 80%), high lactate dehydrogenase (> 1.5 times the upper limit of normal), low serum hemoglobin, high corrected serum calcium (> 10 mg/dL), and time from initial renal tumor diagnosis to IFN-α therapy of less than one year. Each patient was assigned to one of three risk groups: those with zero risk factors (favorable risk), those with one or two risk factors (intermediate risk), and those with three or more risk factors (poor risk). The median time to death was 30, 14, and 5 months in the favorable, intermediate, and poor-risk groups, respectively [13]. These five risk criteria are now most frequently used

In the era of targeted therapy, Heng et al. [14] reported a new prognostic model that added platelet and neutrophil counts to the MSKCC model from a large multicenter study of 645 patients with metastatic renal tumor who were treated with targeted therapy. This study in‐ cluded three groups of patients: 396 patients treated with sunitinib, 200 patients treated with sorafenib, and 49 patients treated with bevacizumab. Four of the five adverse prognostic fac‐ tors according to the MSKCC risk classification−low hemoglobin, high corrected serum cal‐ cium, low Karnofsky PS, and time from the initial renal tumor diagnosis to the start of treatment of less than one year−emerged as independent predictors of poor survival. Addi‐ tionally, platelets greater than the upper limit of normal range, and neutrophils greater than the upper limit of normal range, emerged as independent adverse prognostic factors. MSKCC model with the addition of platelet and neutrophil counts can be incorporated into

C-reactive protein (CRP), a non-specific inflammatory acute-phase protein, is a representa‐ tive marker of systemic inflammatory response. CRP levels correlate with the production of proinflammatory cytokines, such as interleukin (IL) -6 [15], and with tumor progression [16, 17]. It has been recognized as an important prognostic marker in the cytokine era. Atzpo‐

**3. Biomarkers of response to sunitinib in renal tumors**

prognostic model for patients with advanced renal tumor.

patient care of targeted therapies [14].

**3.2. C-reactive protein**

The most important molecular disorder in renal tumors involves the von Hippel-Lindau (VHL) tumor suppressor gene, which is responsible for clear-cell renal tumors. The protein production of the *VHL* gene, which is located on chromosome 3p25, prevents angiogenesis and suppresses tumors [7]. Inactivating the phosphorylated VHL protein activates hypoxiainducible factor (HIF) and the induction of VEGF in clear-cell renal tumors. Mesenchymalepithelial transition factor (MET) and fumarate hydratase (FH) are responsible for papillary renal tumors. While chromophobe renal tumors, Birt-Hogg-Dube (BHD) tumor suppresor gene is mutated [8]. The inherited renal tumor genes *VHL*, *MET*, *FH*, *folliculin*, *succinate dehy‐ drogenase*, tuberous sclerosis complex (TSC) 1, and *TSC2* are all involved in metabolic path‐ ways related to oxygen, iron, energy, and nutrient sensing [9].

Alterations in proto-oncogenes and tumor suppressor genes leads to dysregulated signal transduction that underlies the abnormal growth and proliferation of cancer cells. Signaling proteins that are centrally located in important cancer-associated signaling networks can serve as therapeutic targets [10].

### **2.1. Angiogenetic signaling pathways**

Renal tumors are frequnently characterized by hypoxic conditions. Hypoxia and compensa‐ tory hyperactivation of angiogenesis are thought to be particularly important in renal tu‐ mors, given the highly vascularized nature and the specific association of mutation in *VHL*, a critical regulator of the hypoxic response. Hypoxic signaling is mediated by HIF. Increased expression of HIF target genes is implicated in promoting cancer, inducing both changes within the tumor and changes in the growth of adjacent endothelial cells to promote blood vessel growth. The expression level of VEGF in renal tumors is known to strongly correlate with microvessel density [10].

### **2.2. PI3K/AKT/mTOR pathway**

Mammalian target of rapamycin (mTOR) and protein kinase B (AKT) are key oncogenic process including cell proliferation, survival, and angiogenesis. PI3K promotes the genera‐ tion of phosphatidylinositol-3, 4, 5-triphosphate. Signaling from VEGF and PDGF through AKT activates mTOR. Components of this PI3K/AKT/mTOR pathway are constitutively acti‐ vated in renal tumors compared to normal renal tissues [11].

### **2.3. HGF/MET pathway**

**2. Signaling pathways in renal tumors**

ways related to oxygen, iron, energy, and nutrient sensing [9].

vated in renal tumors compared to normal renal tissues [11].

(approximately 5%) [7].

32 Renal Tumor

serve as therapeutic targets [10].

with microvessel density [10].

**2.2. PI3K/AKT/mTOR pathway**

**2.1. Angiogenetic signaling pathways**

Renal tumors originates from the tubular structures of the kidney and is calssified into four major histological cell types. Clear-cell renal tumor is the most common type, accounting for approximately 75% of all renal tumors. Other types are followed by papillary renal tumor (approximately 15%), chromophobe renal tumor (approximately 5%), and renal oncocytoma

The most important molecular disorder in renal tumors involves the von Hippel-Lindau (VHL) tumor suppressor gene, which is responsible for clear-cell renal tumors. The protein production of the *VHL* gene, which is located on chromosome 3p25, prevents angiogenesis and suppresses tumors [7]. Inactivating the phosphorylated VHL protein activates hypoxiainducible factor (HIF) and the induction of VEGF in clear-cell renal tumors. Mesenchymalepithelial transition factor (MET) and fumarate hydratase (FH) are responsible for papillary renal tumors. While chromophobe renal tumors, Birt-Hogg-Dube (BHD) tumor suppresor gene is mutated [8]. The inherited renal tumor genes *VHL*, *MET*, *FH*, *folliculin*, *succinate dehy‐ drogenase*, tuberous sclerosis complex (TSC) 1, and *TSC2* are all involved in metabolic path‐

Alterations in proto-oncogenes and tumor suppressor genes leads to dysregulated signal transduction that underlies the abnormal growth and proliferation of cancer cells. Signaling proteins that are centrally located in important cancer-associated signaling networks can

Renal tumors are frequnently characterized by hypoxic conditions. Hypoxia and compensa‐ tory hyperactivation of angiogenesis are thought to be particularly important in renal tu‐ mors, given the highly vascularized nature and the specific association of mutation in *VHL*, a critical regulator of the hypoxic response. Hypoxic signaling is mediated by HIF. Increased expression of HIF target genes is implicated in promoting cancer, inducing both changes within the tumor and changes in the growth of adjacent endothelial cells to promote blood vessel growth. The expression level of VEGF in renal tumors is known to strongly correlate

Mammalian target of rapamycin (mTOR) and protein kinase B (AKT) are key oncogenic process including cell proliferation, survival, and angiogenesis. PI3K promotes the genera‐ tion of phosphatidylinositol-3, 4, 5-triphosphate. Signaling from VEGF and PDGF through AKT activates mTOR. Components of this PI3K/AKT/mTOR pathway are constitutively acti‐

Changes in expression and activity of hepatocyte growth factor (HGF) and its receptor c-MET have been associated with renal tumors. HGF binding to MET leads to phosphory‐ lation of two tyrosine residues at the C-terminus of MET, which leads to the recruitment of adapter proteins and activation of PI3K/AKT pathway to promote renal tumor growth and metastasis [12].
