Tumor-associated macrophage-derived CCL5 promotes chemotherapy resistance and metastasis in prostatic cancer.

The crosstalk between tumor microenvironment and cancer cells is emerging as a critical determinant in tumor progression. However, the underlying mechanism of tumor microenvironment-induced cancer development remains controversial. Here, our study provides evidence to suggest that tumor-associated macrophage (TAM) enrichment is found in chemoresistant prostatic tumor tissues. Those TAMs are demonstrated to promote chemoresistance and distant metastasis in prostatic cancer through secretion of CCL5. Mechanistically, TAM coculture or additional CCL5 can mediate the STAT3-dependent epithelial-mesenchymal transition process, resulting in distant metastasis in prostatic cancer. Meanwhile, activation of STAT3 induced by CCL5 can mediate upregulation of the transcription factor Nanog, leading to drug resistance. In vivo study further demonstrated that blockade of STAT3 signals significantly reverses chemoresistance and suppresses lung metastasis in colorectal tumor-bearing mice, suggesting a novel strategy for clinical prostatic cancer treatment.