IL-1ß expression driven by androgen receptor absence or inactivation promotes prostate cancer bone metastasis.

We report the inverse association between the expression of androgen receptor (AR) and interleukin-1beta (IL-1ß) in a cohort of patients with metastatic castration resistant prostate cancer (mCRPC). We also discovered that AR represses the IL-1ß gene by binding an androgen response element (ARE) half-site located within the promoter, which explains the IL-1ß expression in AR-negative (ARNEG) cancer cells. Consistently, androgen-depletion or AR-pathway inhibitors (ARIs) de-repressed IL-1ß in ARPOS cancer cells, both in vitro and in vivo. The AR transcriptional repression is sustained by histone de-acetylation at the H3K27 mark in the IL-1ß promoter. Notably, patients' data suggest that DNA methylation prevents IL-1ß expression, even if the AR-signaling axis is inactive. Our previous studies show that secreted IL-1ß supports metastatic progression in mice by altering the transcriptome of tumor-associated bone stroma. Thus, in prostate cancer patients harboring ARNEG tumor cells or treated with ADT/ARIs, and with the IL-1ß gene unmethylated, IL-1ß could condition the metastatic microenvironment to sustain disease progression.

The dark side of daylight: photoaging and the tumor microenvironment in melanoma progression.

Continued thinning of the atmospheric ozone, which protects the earth from damaging ultraviolet radiation (UVR), will result in elevated levels of UVR reaching the earth's surface, leading to a drastic increase in the incidence of skin cancer. In addition to promoting carcinogenesis in skin cells, UVR is a potent extrinsic driver of age-related changes in the skin known as "photoaging." We are in the preliminary stages of understanding of the role of intrinsic aging in melanoma, and the tumor-permissive effects of photoaging on the skin microenvironment remain largely unexplored. In this Review, we provide an overview of the impact of UVR on the skin microenvironment, addressing changes that converge or diverge with those observed in intrinsic aging. Intrinsic and extrinsic aging promote phenotypic changes to skin cell populations that alter fundamental processes such as melanogenesis, extracellular matrix deposition, inflammation, and immune response. Given the relevance of these processes in cancer, we discuss how photoaging might render the skin microenvironment permissive to melanoma progression.

Limiting tumor seeding as a therapeutic approach for metastatic disease.

Here we propose that therapeutic targeting of circulating tumor cells (CTCs), which are widely understood to be the seeds of metastasis, would represent an effective strategy towards limiting numerical expansion of secondary lesions and containing overall tumor burden in cancer patients. However, the molecular mediators of tumor seeding have not been well characterized. This is in part due to the limited number of pre-clinical in vivo approaches that appropriately interrogate the mechanisms by which cancer cells home to arresting organs. It is critical that we continue to investigate the mediators of tumor seeding as it is evident that the ability of CTCs to colonize in distant sites is what drives disease progression even after the primary tumor has been ablated by local modalities. In addition to slowing disease progression, containing metastatic spread by impeding tumor cell seeding may also provide a clinical benefit by increasing the duration of the residence of CTCs in systemic circulation thereby increasing their exposure to pharmacological agents commonly used in the treatment of patients such as chemotherapy and immunotherapies. In this review we will examine the current state of knowledge about the mechanisms of tumor cells seeding as well as explore how targeting this stage of metastatic spreading may provide therapeutic benefit to patients with advanced disease.