SPP1 (Osteopontin) in drug resistance by various cancers

Drug resistance is one of the major unresolved problems in oncology. Progression mediators, such as SPP1 (Secreted Phosphoprotein 1, Osteopontin, OPN), are often responsible for this phenomenon. PubMed references for SPP1 in cancer drug resistance were studied. The gene product may effectuate unresponsiveness to anti-cancer drug treatment in solid tumors, including carcinomas (breast cancer, cervical and ovarian cancers, prostate cancer, lung cancer, mesothelioma, renal cancer, liver cancer, pancreas cancer, gastric cancer, colon cancer, squamous cell carcinoma), sarcomas (synovial sarcoma, osteosarcoma, GIST, fibrous histiocytoma), and neuroectodermal or neural crest tumors (glioma, melanoma) as well as in hematologic malignancies (acute myeloid leukemia, chronic myelogenous leukemia, multiple myeloma, lymphoma, lymphocytic and lymphoblastic leukemia). The effects are context-dependent, but mostly involve activation of efflux transporters, anti-apoptosis (through autophagy, epithelial-mesenchymal transition, stem cell quiescence), and creation of a pro-survival niche (through microenvironmental effects, immune deviation). Stem-like cells (CD44 + /CD133 + in solid tumors, CD34 + /CD123 + in hematologic malignancies) constitute the subpopulations, through which SPP1 predominantly exerts its drug resistance effects. Stromal cells, including macrophages and fibroblasts, may also secrete SPP1 and contribute to drug resistance phenotypes. Drug classes, to which resistance can be displayed, include immunotherapeutics, anti-angiogenesis drugs, apoptosis inducers, and DNA-damaging agents. Typical for cancer progression genes, SPP1 is aberrantly expressed or spliced in malignant cells, and its variant forms SPP1-b (OPN-b) and SPP1-c (OPN-c) may be most active in conveying drug resistance properties. Common downstream effectors include AKT signaling (anti-apoptosis and epithelial-mesenchymal transition), NF-κB (signals toward anti-apoptosis and stemness, inflammatory response reducing the sensitivity to immune checkpoint blockers), TGF-β, and HIF transcription factors (linking hypoxia to the acquisition and maintenance of stem-cell properties). In some settings, SPP1 does not impact drug resistance, and in rare cases it is associated with positive drug responses.