Tumor-Associated Macrophage Promotes the Survival of Cancer Cells upon Docetaxel Chemotherapy via the CSF1/CSF1R-CXCL12/CXCR4 Axis in Castration-Resistant Prostate Cancer.

Wei Guan,Fan Li,Yan Zhang,Junhui Hu,Zhenyu Zhao,Zongbiao Zhang

doi:10.3390/genes12050773

Abstract

Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer.

Highlights

Prostate cancer is the most common cancer in men and the leading cause of mortality caused by cancer in men after lung and bronchus in the United States in 2021 [1]
Androgen deprivation therapy (ADT) was developed more than 75 years ago and has been the standard of care as first-line therapy. It represents a large category of treatment plans, from surgical orchidectomy initially, to blockage of the androgen receptor (AR) and androgen synthesis pathways through abiraterone and enzalutamide
Some of the patients in the advanced stages of cancer who receive ADT progress to become androgen-independent, in a condition known as castration-resistant prostate cancer (CRPC)

Summary

Introduction

Prostate cancer is the most common cancer in men and the leading cause of mortality caused by cancer in men after lung and bronchus in the United States in 2021 [1]. Nearly 100% of all patients who are in the early stages with a localized or regional primary tumor can be cured, and around 98% of patients overall may receive favorable 5-year survival prognoses [1]. Androgen deprivation therapy (ADT) was developed more than 75 years ago and has been the standard of care as first-line therapy. It represents a large category of treatment plans, from surgical orchidectomy initially, to blockage of the androgen receptor (AR) and androgen synthesis pathways through abiraterone and enzalutamide. Some of the patients in the advanced stages of cancer who receive ADT progress to become androgen-independent, in a condition known as castration-resistant prostate cancer (CRPC)

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