Co-expression of uPAR and CXCR4 promotes tumor growth and metastasis in small cell lung cancer

Urokinase-type plasminogen activator receptor (uPAR) and C-X-C-chemokine receptor-4 (CXCR4) are considered as key molecules in invasion and metastasis of several cancers via extracellular matrix degeneration and assist tumor metastasis to specific sites by chemotaxis. However, the combined effect of uPAR and CXCR4 on small cell lung cancer (SCLC), the most aggressive type of lung cancer, is not clear. In this study, we detected the expression of uPAR and CXCR4 in SCLC tissue samples (n = 50) by immunohistochemistry. The tumors with high expression of both uPAR and CXCR4 (12/50) had larger size, higher lymph node (LN) metastasis and worse prognosis of patients than those with low expression of uPAR and CXCR4 (38/50) (P < 0.05). We further identified and isolated the both uPAR and CXCR4 positive expression subpopulation cells (uPAR+CXCR4+ cells) from the SCLC cell line H446 by flow cytometry. The uPAR+CXCR4+ cancer cells showed a higher invasive and migrating capacity in the transwell and wound healing assays compared with other subpopulation cells (P < 0.05). uPAR+CXCR4+ cells injected subcutaneously in nude mice markedly increased tumor growth and induced lung metastasis, while other subpopulation cells did not. In conclusion, these data suggest that uPAR and CXCR4 co-expression predicts worse prognosis of SCLC patients. uPAR+CXCR4+ cells promote the tumor growth and play a potential role in metastasis of SCLC.