The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

SIMPLE SUMMARY: Prostate cancer is a malignancy that affects a high number of men all over the world. When indolent, prostate cancer can remain silent for years without needing medical intervention. However, aggressive prostate cancer can grow fast, resist treatment, and cause morbidity and ultimately death. Uncovering mechanisms of prostate cancer disease progression and therapy resistance is important to develop new treatments that help patients live longer and healthier. The extracellular matrix, which provides physical support for tissues and organs, is emerging as an important mediator of disease, especially in cancer. In this review, we examine how extracellular matrix alteration, primarily through stiffening, can affect prostate cancer disease course. We look at mechanisms that involve the androgen receptor, which lies at the center of the disease transcriptional landscape, as well as alternative pathways that are androgen receptor-independent. ABSTRACT: Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers. While this process is increasingly well-characterized in breast cancer, a similar in-depth look at ECM stiffening remains lacking for prostate cancer. In this review, we scrutinize the current state of literature regarding ECM stiffening in prostate cancer and its potential association with disease progression and castration resistance.