CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance

Abstract

Metastasis is the primary cause of cancer patient morbidity and mortality but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patients' tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. In our analyses, CD117 was expressed in several tissues and was highly expressed in bone marrow progenitor cells. Also, we uncovered that CD117 gene amplifications and mutations occurred in multiple cancers. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. These signaling pathways were commonly altered in patients with CD117 amplifications and mutations. Here, we examine evidence that the SCF/CD117 signaling axis controls cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors.

Low Molecular Weight Hyaluronic Acid Effect on Dental Pulp Stem Cells In Vitro

“…Similarly, we have observed a statistically significant decrease of CD117 (transmembrane receptor tyrosine kinase, c-KIT) expression in experimental groups. CD117 signaling also affects the Akt pathway and plays a role in cell proliferation, differentiation, adhesion, motility, and angiogenesis in hematopoietic cells and cancer stem-like cells [ 64 , 65 ]. Our data show the downregulation of both of these membrane proteins related to proliferation, mobility, and differentiation in DPSCs cultivated in LMW-HA enriched media.…”

The Emerging Role of PPAR Beta/Delta in Tumor Angiogenesis

“…Protooncogene c-KIT/CD117 is known as the mast/stem cell factor receptor and receptor tyrosine kinase, and its activation in CSCs may regulate the stemness to control tumor progression and drug resistance to tyrosine kinase inhibitors. Moreover, c-KIT has been identified as a potential marker of the cancer stem-like cells [152]. In addition, c-KIT not only functions on ECs [153,154] but also belongs to the tumor angiogenesis-promoting molecule [155][156][157][158].…”

“…Forkhead box protein O1 (FOXO1) is required for EC proliferation and vascular growth [196,198], and directly regulates VEGFA expression during wound healing [197]. In addition to the physiological angiogenesis, FOXO1 is suggested to be involved in developmental and pathological angiogenesis c-KIT A potential marker of cancer stem-like cells [152]; promotion of tumor angiogenesis [155][156][157][158] and pathological ocular neovascularization [161] [16]…”

Involvement of the Estrogen and Progesterone Axis in Cancer Stemness: Elucidating Molecular Mechanisms and Clinical Significance

“…CXC chemokine receptor 4 (CXCR4) is an another stemness-related biomarker associated with tumor growth, invasion, metastasis, and relapse (39,52). Moreover, cell surface markers such as CD24, CD26, CD44, CD90, CD133, CD166, CD177, aldehyde dehydrogenase 1 (ALDH1), and epithelial cell adhesion molecule (EPCAM) have been identified as biomarkers of CSCs in various types of cancers (39,(53)(54)(55). Table 1 presents a summary of the currently known CSC biomarkers and their characteristics.…”