12/10/2022 0 Comments Signal transduction![]() ![]() Such information is vital to the reawakening of ‘systems biology’. The challenge in the future will be to better understand how signal specificity is achieved. Signal transduction is now thought to occur through tightly organized networks in which protein–protein interactions and reversible assembly of signaling complexes are controlled by a small number of modular domains. During the past 50 years, intensive research uncovered the enzymes and molecules that participate in this process (i.e., receptors, second messengers, phospholipases, kinases, phosphatases, etc.) and delineated the mechanisms by which cells integrate multiple signals. Signal transduction refers to all biochemical processes by which cells translate extracellular signals originating from their environment into specific responses. Forman, in Encyclopedia of Respiratory Medicine, 2006 Cabozantinib, an inhibitor of VEGFR, MET, and AXL, demonstrated a significant clinical benefit versus sunitinib, which primarily targets VEGFR, as first-line treatment for intermediate- to poor-risk RCC, suggesting a potential superiority to dual pathway inhibition ( Choueiri et al., 2017a). Increased serum levels of hepatocyte growth factor have also been reported in most patients with RCC, independent of histologic subtype, and activation of the receptor by phosphorylation at two sites is associated with cancer progression, making c- Met a potential therapeutic target for papillary and other forms of RCC ( Gibney et al., 2013). Hepatocyte growth factor is expressed by normal proximal tubular cells, where it is involved in branching tubulogenesis of the developing kidney and regeneration after renal injury. The role of activating mutations of the c- MET proto-oncogene in the cause of hereditary papillary RCC has already been discussed, but data suggest that upregulated expression of this ligand may also occur in most of the histologic subtypes of RCC ( Giubellino et al., 2009 Harshman and Choueiri, 2013). The hepatocyte growth factor and its receptor, the c- MET proto-oncogene, may also contribute to the pathogenesis of RCC ( Gibney et al., 2013 Giubellino et al., 2009 Harshman and Choueiri, 2013). Based on these results, agents targeting the EGFR pathway have fallen out of favor for RCC, although selective treatment of patients who overexpress EGFR may still be a consideration within precision medicine trials. Unfortunately, phase II clinical trials using agents that target EGFR, including erlotinib (Tarceva), gefitinib (Iressa), panitumumab (Vectibix), and lapatinib (Tykerb), demonstrated a lack of substantial activity in patients with advanced RCC ( Rini, 2010). Increased expression of transforming growth factor-α and its receptor tyrosine kinase, the epidermal growth factor receptor (EGFR), have been reported in RCC and may contribute to tumorigenesis by promoting cellular proliferation or transformation through an autocrine mechanism. ![]() ![]() Proliferative index, as defined by proliferating cell nuclear antigen or Ki-67 staining, has correlated with pathologic parameters and clinical outcomes in RCC, suggesting that regulation of the cell cycle plays an important role in the tumor biology of RCC ( Bui et al., 2004 Tollefson et al., 2007). Both of these mTOR inhibitors are now also approved by the FDA. Inhibition of mTOR with temsirolimus (Torisel) has yielded prolonged survival in patients with poor-risk, metastatic RCC, and everolimus (Afinitor) has shown efficacy for patients in whom tyrosine kinase inhibitors have failed, confirming the clinical relevance of the mTOR pathway (see Fig. Through complex pathways involving a variety of intermediaries, the mTOR pathway leads to increased expression of HIFs and other growth-promoting and potentially tumorigenic sequelae. Expression of mTOR is upregulated by various growth factors or by mutation or loss of PTEN. One such regulatory pathway in RCC is the mTOR pathway, which interfaces with Akt (protein kinase B) and the PTEN tumor suppressor gene ( Barthelemy et al., 2013 Hudes, 2009). Partin MD, PhD, in Campbell-Walsh-Wein Urology, 2021 Other Signal Transduction and Cell Cycle Regulation PathwaysĪberrant activation of additional signal transduction pathways in RCC may also contribute to altered cell cycle kinetics, and these pathways represent excellent targets for therapeutic intervention. ![]()
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