title: Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs.
abstract: Bone metastasis is a main cause of cancer-related mortality in patients with advanced prostate cancer. Emerging evidence suggests that the acidic extracellular microenvironment plays significant roles in the growth and metastasis of tumors. However, the effects of acidity on bone metastasis of PCa remain undefined. In the present study, PC-3 cells were cultured in acidic medium (AM; pH 6.5) or neutral medium (NM; pH 7.4), aiming to investigate the effects and possible mechanisms of acidic extracellular microenvironment in bone metastasis of PCa. Our results showed that AM can promote spheroid and colony formations, cell viability and expression of stem cell characteristic-related markers in PC-3 cells. Moreover, AM stimulates MMP-9 secretion and promotes invasiveness of PC-3 cells, and these effects can be inhibited by blocking of MMP-9. Furthermore, AM stimulates VEGF secretion of PC-3 and AM conditioned medium (CMAM) promotes vasculogenesis of BM-EPCs by increasing cell viability, migration, tube formation, which involved activating the phosphorylation of VEGFR-2, Akt and P38, when pH of NM conditioned medium (CMNM) was modulated the same as AM conditioned medium (CMAM). Further studies have shown that CMNM induced vasculogenesis of BM-EPCs can be inhibited by the inhibition of VEGFR2 with DMH4. These findings suggest that acidic extracellular microenvironment may have the potential to modulate prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs. Improved anticancer strategies should be designed to selectively target acidic tumor microenvironment.
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Sheng
authors: S
authors: Huang
authors: Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Yubo
authors: Y
authors: Tang
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Xinsheng
authors: X
authors: Peng
authors: Department of Respiratory Disease, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510000, P.R. China.
authors: Xingdong
authors: X
authors: Cai
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Qingde
authors: Q
authors: Wa
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Dong
authors: D
authors: Ren
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Qiji
authors: Q
authors: Li
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Jiaquan
authors: J
authors: Luo
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Liangping
authors: L
authors: Li
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Xuenong
authors: X
authors: Zou
authors: Department of Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute/Orthopaedic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
authors: Shuai
authors: S
authors: Huang
mesh_terms: D000328:Adult; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D066026:Endothelial Progenitor Cells / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D059016:Tumor Microenvironment