A juxtacrine/paracrine loop between C-Kit and stem cell factor promotes cancer stem cell survival in epithelial ovarian cancer

Abstract

Receptors tyrosine kinase (RTK) enable normal and tumor cells to perceive and adapt to stimuli present in the microenvironment. These stimuli, also known as growth factors, are important molecular cues actively supporting cancer stem cell (CSC) self-renewal and viability. Since in epithelial ovarian cancer (EOC) the expression of c-Kit (CD117) has been identified as a CSC hallmark, we investigated the existence of a tumor growth-promoting loop between c-Kit and its ligand Stem Cell Factor (SCF). SCF exists as a soluble or transmembrane protein and through c-Kit interaction regulates cell viability, proliferation, and differentiation both in physiological and pathological conditions. High amounts of SCF were found in the ascitic effusions collected from EOC patients. While tumor cells and CSC only expressed the membrane-associated SCF isoform, both secreted and membrane-bound isoforms were expressed by tumor-associated macrophages (TAM, here shown to be M2-like) and fibroblasts (TAF). Circulating monocytes from EOC-bearing patients and healthy donors did not express both SCF isoforms. However, monocytes isolated from healthy donors produced SCF upon in vitro differentiation into macrophages, irrespectively of M1 or M2 polarization. In vitro, both SCF isoforms were able to activate the Akt pathway in c-Kit + cells, and this effect was counteracted by the tyrosine kinase inhibitor imatinib. In addition, our results indicated that SCF could help c-Kit + CSC survival in selective culture conditions and promote their canonical stemness properties, thus indicating the possible existence of a juxtacrine/paracrine circuit in EOC.

Liquid biopsy based on small extracellular vesicles predicts chemotherapy response of canine multicentric lymphomas

“…SCF-kit is the complex composed by ligand SCF and tyrosine kinase receptor c-Kit. The gene c-Kit is a proto-oncogene that is subject to dysregulation and gain-of-function mutations and amplifications that promote tumorigenesis in a variety of tumor types 46 . However, c-Kit can also promote apoptosis and inhibit tumor growth in absence of SCF (stem cell factor) 47 .…”

Macrophages in Oral Carcinomas: Relationship with Cancer Stem Cell Markers and PD-L1 Expression

“…In addition, CSCs may exert a strong immune suppressive effect by suppressing the Major Histocompatibility Complex (MHC) by macrophages in the TME, releasing the exosomal miRNAs miR-9 and miR-21, or by secreting VEGF that plays a pivotal role in tumor angiogenesis and suppression of T-cell maturation [ 35 ]. Mazzoldi et al [ 36 ] found that, the c-Kit ligand Stem Cell Factor (SCF), produced by M2 macrophages, may favor the immune escape of tumor cells in ovarian cancer. Similarly, ovarian CSCs and macrophages reciprocally interact through the WNT/β-catenin signaling, thereby contributing to tumorigenesis, invasiveness, and immune suppression [ 37 ].…”

Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration

“…Two µg of the total RNA, extracted from spheroids with TRIzol Q16 reagent (Invitrogen, Carlsbad) was reverse transcribed and then subjected to PCR with enzymes and reagents of the RTplusPCR system (Eppendorf, Hamburg, Germany) using GeneAmpPCR 2720 (Applied Biosystems, CA, USA) 56 . The cDNAs were amplified with primers specific for mTOR (5′-GTCATCCAACGGGAATGCA-3′/5′- TGATCGGTTACCGTGATCAAAA-3′), GAPDH (internal control): (5′-CAGAACATCATCCTGCCTCT- 3′/ 5′-GCTTGACAAAGTG GTCGTTGAG-3′) 13 .…”

“…Extracted DNA (2 µl) was used for 45 cycles of amplification in 20 µl of reaction mixture under the following conditions: 95 °C for 30 s, 56 °C for 30 s, and 72 °C for 60 s 56 . The PCR products were subjected to electrophoresis using 2% agarose gel 56 .…”