Activation PDGFR-α/AKT Mediated Signaling Pathways in Oral Squamous Cell Carcinoma by Mesenchymal Stem/Stromal Cells Promotes Anti-apoptosis and Decreased Sensitivity to Cisplatin

Abstract

Desmoplasia, a hallmark of a head and neck cancer, has both biologic and physiologic effects on cancer progression and chemotherapeutic response. Mesenchymal stem/stromal cells (MSCs), also known as mesenchymal stromal progenitor cells, have been shown to play a role in cancer progression, alter apoptotic responses, and confer resistance to chemotherapy in various carcinomas. The pathophysiology of MSCs with respect to tumorigenesis is widely reported in other cancers and is sparsely reported in oral squamous cell carcinomas (OSCCs). We previously reported paracrine mediated PDGF-AA/PDGFR-α signaling to underlie MSCs chemotaxis in OSCC. Given the poor clinical response to primary chemotherapy, we hypothesized that MSCs may alter cancer cell sensitivity to cisplatin through activation of PDGFR-α mediated signaling pathways. Co-culture of MSCs with human derived OSCC cell lines, JHU-012 and −019, resulted in a significant increase in the production of PDGF-AA and MCP-1 compared to cancer cells grown alone (p < 0.005) and was accompanied by an increase in the phosphorylation state of PDGFR-α (p < 0.02) and downstream target AKT at S473 (p < 0.025) and T308 (p < 0.02). JHU-012 and −019 cancer cells grown in co-culture were significantly less apoptotic (p < 0.001), expressed significantly higher levels of Bcl-2 (p < 0.04) with a concomitant significant decrease in bid expression (p < 0.001) compared to cancer cells grown alone. There was a significant increase in the cisplatin dose response curve in cancer cell clones derived from JHU-012 and 019 cancer cells grown in co-culture with MSCs compared to clones derived from cancer cells grown alone (p < 0.001). Moreover clones derived from JHU-012 cells grown in co-culture with MSCs were significantly more susceptible to cisplatin following pretreatment with, crenolanib, a PDGFR inhibitor, Wang et al. PDGFR-α/AKT Signaling in Oral Cancer compared to cancer cells grown alone or in co-culture with MSCs (p < 0.0001). These findings suggest that crosstalk between cancer cells and MSCs is mediated, at least in part, by activation of autocrine PDGF-AA/PDGFR-α loop driving AKT-mediated signaling pathways, resulting in reduced cancer cell sensitivity to cisplatin through alterations in apoptosis.

Epithelial-to-Mesenchymal Transition-Derived Heterogeneity in Head and Neck Squamous Cell Carcinomas

“…Chemoattractants such as CXCL1 may help in recruiting non-malignant supportive cells such as neutrophils, which have ample functions as tumor-associated neutrophils (TANs) in the tumor environment [ 125 ]. Furthermore, platelet-derived growth factor receptors alpha and beta (PDGFR-A/B) have been associated with an induction of resistance to cisplatin, anti-apoptotic traits, and metastases formation [ 126 , 127 ]. Four out of eight gene sets enriched in low-risk patients were associated with mRNA metabolism and cell cycle regulation [ 123 ], which could potentially explain a better response to R(C)T in cycling cells and subsequent reduction of recurrences.…”

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

“…Platelet-derived growth factor receptor alpha (PDGFRA) gene encodes a tyrosine kinase receptor that activates tyrosine kinase (Ong et al 2018). It has been shown that PDG-FRA is involved in gene mutation, tumor cell proliferation, migration and invasion, maintenance of mesenchymal stromal cells (MSC), and immune infiltration, while it may serve as a potential biomarker and therapeutic target (Chang et al 2018;Pantaleo et al 2019;Wang et al 2020a PDGFRA signaling is sufficient to drive fibrosis in diverse organs. Targeting PDGFRA signaling can be an effective approach to treat fibrosis (Decker et al 2017).…”

Potential of Moringa oleifera extract-incorporated with folic acid-conjugated gold nanoparticles as an oral squamous cell carcinoma therapy by modulating intrinsic apoptotic pathway: A narrative review

“…[42,43] Akt is inactivated by disrupting phosphorylation process of T308 and S473 which causes a decrease in the catalytic process and inactivation manifests in decreased expression of Bcl-2 as an anti-apoptotic protein. [44,45] A decrease of Bcl-2 accompanied by downregulation of Bcl-XL and MCL-1 leads to activation of Bcl-2 homologous antagonist killer (Bak) by BH3 on the mitochondrial outer membrane. [46] The activation of Bak may also be caused by an increase of BH3-interacting-domain death agonist (Bid) and p53 upregulated modulator of apoptosis (Puma).…”