Abstract
The incidence of prostate cancer is directly linked to age, but age-associated changes that facilitate prostate cancer development and progression are poorly understood. This study investigated age-related changes in the prostate microenvironment for their influence on prostate cancer behavior. Prostate cancer cells implanted orthotopically into the prostate demonstrated accelerated tumor growth in aged compared with 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 IHC and RNA sequencing (RNA-seq) revealed elevated numbers of macrophages in prostates from aged mice, which are quickly polarized towards a phenotype resembling protumorigenic tumor-associated macrophages upon tumor cell engraftment. Older patients with prostate cancer (>60 years old) in The Cancer Genome Atlas Prostate Adenocarcinoma (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 prostate cancer growth and invasion in the aged microenvironment. Moreover, the collagen matrix extracted from aged mice enhanced the invasiveness and proliferation of prostate cancer 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 protumorigenic phenotype, along with remodeling of the ECM. IMPLICATIONS: These findings demonstrate the importance of age-associated tumor microenvironment alterations in regulating key aspects of prostate cancer progression.
Highlights
Organismal aging is associated with a spectrum of molecular, cellular, and physiologic changes that contribute to increasing homeostatic imbalance and the development of diseases such as cancer
The prostate microenvironment in aged mice promotes the growth of orthotopic tumors To test the direct contribution of the aged prostatic microenvironment toward the growth of prostate cancer cells, we injected 106 TRAMP-C2 cells, a cell line derived from a tumor developing in a genetically engineered mouse (GEM) model expressing the SV40T antigen in mouse prostate epithelium [12], into the dorsolateral prostate of immune-competent syngeneic young (4 month-old; n 1⁄4 20) and aged (20–24 month-old; n 1⁄4 19) C57BL/6 mice
The objectives of this study were to test the direct effects of the aged prostate microenvironment on the growth of prostate cancer cells and metastatic spread
Summary
Organismal aging is associated with a spectrum of molecular, cellular, and physiologic changes that contribute to increasing homeostatic imbalance and the development of diseases such as cancer. A major contributor to prostate cancer development involves events intrinsic to epithelial cells encompassing DNA mutations, chromosomal gains and losses, and gene rearrangements, it is . Experiments using rodent and rodent/human in vivo and in vitro coculture models support the idea that paracrine interactions between the luminal epithelial cells and the reactive adjacent stroma cells play an important role in the development of benign prostatic hyperplasia (BPH) and prostate cancer [2, 3]. In vitro experiments have demonstrated that cellular and molecular alterations in the prostate microenvironment including those associated with stromal aging and senescence can promote neoplastic progression [4,5,6]
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