Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1α-mediated VEGF-dependent angiogenesis

Abstract

Hypoxia is a salient feature of most solid tumors, and hypoxic adaptation of cancer cells has crucial implications in propagation of malignant clonal cell population. Osteopontin (OPN) has been identified as a hypoxia-responsive gene, but the mechanistic and regulatory role of OPN under hypoxia is less characterized. The present study identifies the existence of a positive inter-regulatory loop between hypoxia and OPN. We have shown that hypoxia induces OPN expression in breast cancer cells; however, the expression was found to be HIF1α independent. OPN enabled transcriptional upregulation of HIF1α expression both under normoxia and hypoxia, whereas stability of HIF1α protein in breast cancer cells remained unaffected. Moreover, we have shown that OPN induces integrin-linked kinase (ILK)/Akt-mediated nuclear factor (NF)-κB p65 activation leading to HIF1α-dependent vascular endothelial growth factor (VEGF) expression and angiogenesis in response to hypoxia. These in vitro data are biologically important as OPN expressing cells induce greater tumor growth and angiogenesis through enhanced expressions of proangiogenic molecules as compared with control. Immunohistochemical analysis of human breast cancer specimens revealed significant correlation between OPN and HIF1α but not HIF2α. Elevated expression of HIF1α and OPN was observed in pre-neoplastic and early stage infiltrating ductal carcinoma implicating the role of these proteins in neoplastic progression of breast cancer. Together, our results substantiate the prime role of OPN in cellular adaptation through ILK and NF-κB-mediated HIF1α-dependent VEGF expression in response to hypoxia that ultimately controls breast cancer progression and angiogenesis. Our study reinforces the fact that targeting OPN and its regulated signaling network hold important therapeutic implications.

Brain-derived neurotrophic factor regulates cell motility in human colon cancer

“…VEGF is upregulated in response to hypoxia, activated oncogenes, and a variety of cytokines (Sismanopoulos et al 2012, Raja et al 2014. VEGF stimulates normal epithelial cells and differentiated carcinoma cells by inducing epithelial-mesenchymal transition (EMT) (Bates et al 2003).…”

Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy

“…5 Production of VEGF by tumor cells can be disproportionately upregulated via oncogenic activation or loss of tumor suppressor function 6,7 and hypoxia or glucose level change. 8 The amount of VEGF-A expressed by tumor cells correlates with poor prognosis in many types of tumors including lung, gastric, colon, prostate, ovary and melanoma. [9][10][11][12][13][14] Of the 3 closely related members of the VEGFR family (VEGFR1, 2, 3), VEGFR2 (also named as KDR or Flk1) and VEGFR3 mainly expressed in vascular and lymphatic endothelial cells, plays major roles in VEGF-A and VEGF-C induced angiogenesis and lymphangiogenesis.…”

Interactions between osteopontin and vascular endothelial growth factor: Implications for cancer

“…This results in breast tumor growth and angiogenesis [12,84]. OPN suppression in breast cancer cells decreases the levels of HIF-1α and VEGF and increases the radiosensitivity of these cells [85].…”

“…Both are present in the secretome (a promising source of blood-based biomarkers) of IGF1R transformed fibroblasts [98]. OPN and VEGF contribute to tumor progression [8,12,19,20,62,[99][100][101][102] and angiogenesis [11,12,16,21,28,37,93,99,100,[103][104][105][106][107][108]. The inhibition of OPN may reduce VEGF levels and suppress tumor progression [85,[109][110][111][112].…”

“…Past studies have found that under specific conditions these proteins may be coexpressed [1][2][3][4][5][6][7][8][9][10], OPN can induce VEGF [11][12][13][14][15][16][17][18][19][20][21], or VEGF can induce OPN [22][23][24][25][26][27][28][29][30][31][32], and both molecules can function in synergy. In other cases, OPN and VEGF act mutually independently [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51].…”