Around 40% of men and women will be diagnosed with cancer at some point in their life, with a median age at diagnosis of 66. Age is the predominant overall risk factor for cancer. However, the incidence of some malignancies is directly correlated with age, especially prostate cancer. Dr. Peter Nelson (Human Biology and Clinical Desearch divisions), the senior author of a study published this month in Molecular Cancer Research, says that “the precise role of aging in advancing tumorigenesis is not established, beyond the intrinsic events of the accumulation of mutations in the tumor cells themselves”. In Dr. Nelson’s labortory’s recent publication, Bianchi-Frias and colleagues propose that the prostate microenvironment becomes more permissive to tumor development with age due to a pro-tumorigenic immune switch and collagen remodeling.
The authors injected tumor cells orthotopically in the prostate of young (4 month-old) and old (20-24 month-old) syngeneic mice (mice of the same genetic background than the tumor cells) and observed that not only were the tumors growing faster in aged animals compared to young ones, but also that the proportion of mice developing metastases was drastically increased. Surprisingly, they did not observe any difference of proliferation, apoptosis, or angiogenesis in tumors developing in young compared to old animals. Dr. Nelson’s team redirected their focus to the immune composition of the tumor to determine to what extent a defect in immune recognition could explain the increased tumor aggressiveness in old mice. They found that although most tumor-infiltrating immune populations were unchanged in both conditions, macrophages were polarized towards a pro-tumorigenic phenotype in the microenvironment of old tumor-bearing mice, with an increased proportion of macrophages expressing Arginase 1 (ARG1). They confirmed by RNAseq that macrophage markers associated with pro-tumorigenesis, such as CD163, Lyve1 or Retnla (in addition to ARG1), were upregulated in old mice tumors. Most importantly, the analysis of prostate cancer patient data from TCGA (The Cancer Genome Atlas) dataset demonstrated that patients over 60 years display an increase in expression of tumor-promoting macrophage markers, and that high tumor expression of the macrophage markers CD163 and VSIG4 corresponds to a decrease in median survival. This supports the clinical relevance of their finding in the animal model. Finally, the authors observed an increased collagen density in old tumor-bearing mice. To understand the effect of such a remodeling on tumor cell behavior, they built 3D gels in vitro using mouse tendon collagen from either young or old mice. As anticipated, proliferation and invasion potential of prostate tumor cells were increased when co-cultured with the collagen isolated from old mice compared to young mice.
This work suggests that prostate cancer cells highjack the different compartments of the aged prostate microenvironment (macrophages, collagen, etc.) to grow and escape immune surveillance, an exciting result that adds up to the complexity of this cancer. However, the authors are still investigating the molecular and cellular mechanisms leading to the establishment of this favorable niche for the tumor cells to proliferate and invade. “We had expected to find an increase in [fibroblast] cellular senescence and the production of cytokines from these senescent cells”, commented Dr. Peter Nelson, “but we did not explicitly observe this”. The understanding of these processes could lead to the identification of potential therapeutic targets for preventive and curative strategies.
This work was supported by Fred Hutch/University of Washington Cancer Consortium, the National Institute of Health and the Department of Defense/Congressionally Directed Medical Research Programs (DoD/CDMRP).
Bianchi-frias D, Damodarasamy M, Hernandez SA, Gil da Costa RM, Vakar-Lopez F, Coleman IM, Reed MJ, Nelson PS. 2018. The Aged Microenvironment Influences theTumorigenic Potential of Malignant Prostate Epithelial Cells. Molecular Cancer Research. DOI: 10.1158/1541-7786.MCR-18-0522