The Aged Microenvironment Influences the Tumorigenic Potential of Malignant Prostate Epithelial Cells.

Publication Type:

Journal Article


Molecular cancer research : MCR (2018)


Genomics Core Facility, Scientific Imaging Core Facility


The incidence of prostate cancer (PC) is directly linked to age, but age-associated changes that facilitate PC development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on PC behavior. PC cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared to young mice. Metastatic lesions following intravenous injection were also more numerous in aged mice. Tumors from young and aged mice showed no significant differences concerning their proliferation index, apoptosis or angiogenesis. However, analysis of tumor-infiltrating immune cells by immunohistochemistry (IHC) and RNA-sequencing (RNA-seq) revealed elevated numbers of macrophages in prostates from aged mice, which are quickly polarized towards a phenotype resembling pro-tumorigenic tumor-associated macrophages (TAMs) upon tumor cell engraftment. Older PC patients (>60 years old) in The Cancer Genome Atlas (TCGA) PRAD dataset displayed higher expression of macrophage markers (CD163 and VSIG4) which associated with higher rates of biochemical relapse. Remodeling of the collagenous extracellular matrix (ECM) was associated with PC growth and invasion in the aged microenvironment. Moreover, the collagen matrix extracted from aged mice enhanced the invasiveness and proliferation of PC cells in vitro. Together, these results demonstrate that the aged prostatic microenvironment can regulate the growth and metastasis of malignant prostate cells, highlighting the role of resident macrophages and their polarization towards a pro-tumorigenic phenotype, along with remodeling of the ECM. IMPLICATIONS: These findings demonstrate the importance of age-associated tumor microenvironment (TME) alterations in regulating key aspects of prostate cancer progression.