Osteopontin promotes cancer cell drug resistance, invasion, and lactate production and is associated with poor outcome of patients with advanced non-small-cell lung cancer

Abstract

BackgroundOsteopontin (OPN), a member of the small integrin binding ligand N-linked glycoprotein family, has been analyzed in numerous types of human malignancy.PurposeThe present study detected the expression levels of OPN and evaluated its role in tumor progression in patients with non-small cell lung cancer (NSCLC).Patients and methodsOPN expression levels were detected using immunohistochemistry in 101 NSCLC tumors. The mRNA and protein levels have significant difference between advanced NSCLC and stage I/II NSCLC. The drug resistance, invasive ability and lactate production of NSCLC cancer cell lines (A549 and SK-MES-1) were detected in cancer cells with the disturbance of OPN.ResultsImmunostaining indicated that OPN was primarily expressed in the cytoplasm of NSCLC cells. Moreover, OPN correlates with NSCLC clinical traits. The results demonstrated that OPN expression levels significantly correlated with cancer differentiation, distant metastasis and the efficacy of platinum-based treatment. Notably, the results identified OPN expression levels as a potential factor for predicting the response of cells to first-line platinum-based chemotherapy using multivariate analysis, as well as predicting cancer differentiation and distant metastasis. Additionally, the abrogation of OPN levels reduced lactate production in NSCLC cells and occurred along side with the downregulation of lactate dehydrogenase A (LDHA).ConclusionThe results of the current study suggest that OPN may be able to predict poor prognosis and cisplatin resistance in patients.

Osteopontin drives KRAS-mutant lung adenocarcinoma

“…In the present study, we investigated the functional role of SPP1 in autochthonous airway epithelial carcinogenesis induced by two different tobacco chemicals and by oncogenic mutant KRAS G12D . In accord with previous studies, analyses of multiple published datasets confirmed the marked (>25-fold) overexpression of SPP1 in LADC compared with adjacent non-tumorous lung tissues, as well as its importance in predicting poor survival [13,[38][39][40].…”

“…Notwithstanding a potential tumor-promoting effect of immune-derived SPP1 in lung cancer not evident in the bone marrow transplant model employed here, our studies highlight the prime mechanism of the pro-tumorigenic functions of SPP1 in the lungs: SPP1 expressed by the tumor-initiated pulmonary epithelium promotes the survival of transformed cells that harbor KRAS mutations. To this end, recent and earlier studies in patients with lung cancer have underlined SPP1 as a peripheral blood biomarker of disease progression and response to therapy[38][39][40]45,46] and their findings can be explained by the tissue-restricted effects of epithelial SPP1 reported here. The latter can be explained by different isoforms of SPP1 potentially secreted by epithelial and myeloid cells, as well as the differential effects of the cytokine depending on cellular TP53 mutation status[11].…”

Osteopontin: A Key Regulator of Tumor Progression and Immunomodulation

“…Angiogenesis, degradation of ECM, the formation of lamellipodia, and switching phenotypes towards either cancer-associated fibroblasts or stem cells are ways in which OPN can promote invasion and metastasis. In lung, breast, colorectal, and head and neck cancer, OPN has been implicated in treatment resistance [ 36 , 102 , 103 , 104 , 105 , 106 ]. The following sections focus on the involvement of OPN in specific cancer types.…”

Osteopontin as a Link between Inflammation and Cancer: The Thorax in the Spotlight

“…During carcinogenesis, OPN upregulates PD-L1 and M2-polarized tumor-associated macrophages and facilitates tumor immune escape, further enhancing pro-tumor activity [66]. It promotes cancer cell drug resistance and invasion in patients with advanced NSCLC and facilitates the development of small-cell lung cancer (SCLC) cells by inhibiting apoptosis and autophagy [114,115]. Recent studies suggest that fibrocytes that are differentiated from bone marrow-derived CD14 + monocytes have features of both macrophages and fibroblasts and may promote cancer progression.…”