Disturbances in Nitric Oxide Cycle and Related Molecular Pathways in Clear Cell Renal Cell Carcinoma

Abstract

It is important to note that maintaining adequate levels of nitric oxide (NO), the turnover, and the oxidation level of nitrogen are essential for the optimal progression of cellular processes, and alterations in the NO cycle indicate a crucial step in the onset and progression of multiple diseases. Cellular accumulation of NO and reactive nitrogen species in many types of tumour cells is expressed by an increased susceptibility to oxidative stress in the tumour microenvironment. Clear cell renal cell carcinoma (ccRCC) is a progressive metabolic disease in which tumour cells can adapt to metabolic reprogramming to enhance NO production in the tumour space. Understanding the factors governing NO biosynthesis metabolites in ccRCC represents a relevant, valuable approach to studying NO-based anticancer therapy. Exploring the molecular processes mediated by NO, related disturbances in molecular pathways, and NO-mediated signalling pathways in ccRCC could have significant therapeutic implications in managing and treating this condition.

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer

“…This free radical is implicated in driving three key factors associated with unfavorable clinical outcomes in cancer: metastasis, resistance to chemo and radiotherapy, and immune suppression [ 8 , 37 , 38 ]. While some studies suggest positive effects of NO [ 39 , 40 , 41 ], the majority link high NOS2 expression to poor survival across a spectrum of hematological and solid tumors, including breast [ 8 ], pancreatic [ 42 ], nasopharyngeal carcinoma [ 43 ], colorectal [ 44 , 45 ], gastric [ 46 ], esophageal [ 47 ], prostate [ 48 ], melanoma [ 49 ], Hodgkin’s lymphoma [ 50 ], ovarian [ 51 ], squamous cell carcinoma [ 52 ], renal cell carcinoma [ 53 ], glioma [ 54 ], chondrosarcomas [ 55 ], Barrett’s esophageal adenocarcinoma [ 56 ], and in HCV-infected liver cancer patients [ 57 ].…”

The Cellular Stress and Cutaneous Manifestations in Renal Cell Carcinomas—A Narrative Review

“…In recent decades, significant progress has been made in understanding the genetic and molecular mechanisms responsible for the development of renal tumors, which has led to improvements in patient care. Deregulated metabolism and oxidative stress pathways are commonly found in renal tumors and are essential factors influencing the progression of renal cell carcinoma (RCC) [1][2][3][4].…”

“…Transitional cell carcinomas, originating in the renal pelvis, make up 8%. The most common subtypes of RCC are clear cell carcinomas (ccRCCs) (70%), papillary RCC (pRCC) (10%), and chromophobe RCC (chRCC) (5%), each with distinct genetic bases and phenotypes [1,2]. ccRCC is characterized in 90% of cases by von Hippel-Lindau (VHL) gene mutation.…”

Clear Cell Renal Cell Carcinoma: A Test Bench for Investigating Tumor Complexity

“…Here, basic researchers and clinicians from Italy, Japan, USA, Spain, South Africa, Sweden, Romania, and Germany present their findings from very different perspectives, i.e., the role of the complement system in the immune background of tumors [4], imagingbased biomarker identification [5], the relevance of the immune microenvironment [6,7], the influence of clock genes and the circadian rhythm in tumor therapy [8], the morphological/molecular characteristics of cystic CCRCCs [9], the single-cell RNA-sequencing signature of primary and metastatic neoplasms [10], an extensive review of tumor biomarkers in CCRCC [11], the nitric oxide cycle-related pathways of this tumor [12], the current trends and complications of partial and radical nephrectomy in CCRCC [13], the characteristics of the intratumor immune heterogeneity in non-metastatic tumors [14], the importance of NPC1 targeting in CCRCC [15], and a comparison between the efficacy of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI)/everolimus in the adjuvant therapy of CCRCC [16].…”

“…Ene et al [12] analyze the role of the nitric oxide (NO) in the therapy of CCRCC. The authors review fundamental aspects such as the disruption of NO homeostasis, the dysregulation ureagenic cycle, the upregulation of glutamine, the cellular depletion of arginine, hyperammonemia, the reduction in branched-chain amino acids, the inactivation of VHL and the accumulation of HIFs, and the endogenous inhibition of NO synthesis.…”