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

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.

The Potential of Extracellular Matrix- and Integrin Adhesion Complex-Related Molecules for Prostate Cancer Biomarker Discovery

“…A frequent characteristic of different tumor types, including those of the lung, breast, colon, pancreas, and liver, is increased tumor stiffness, which is a consequence of excessive deposition of ECM components, especially type I collagen. Among the properties that are affected by increased tumor stiffness are tumor initiation, growth, invasion, metastasis, immune cell infiltration, stem cell differentiation, growth factor secretion and signaling, and angiogenesis and vessel permeability [115]. In prostate cancer, increased tumor stiffness has also been documented and correlated with more malignant tumors with a higher Gleason score (reviewed in [115]).…”

“…Among the properties that are affected by increased tumor stiffness are tumor initiation, growth, invasion, metastasis, immune cell infiltration, stem cell differentiation, growth factor secretion and signaling, and angiogenesis and vessel permeability [115]. In prostate cancer, increased tumor stiffness has also been documented and correlated with more malignant tumors with a higher Gleason score (reviewed in [115]). Signaling pathways activated by ECM stiffness and linked to castration resistance mechanisms in prostate cancer have been recently reviewed [115].…”

“…In prostate cancer, increased tumor stiffness has also been documented and correlated with more malignant tumors with a higher Gleason score (reviewed in [115]). Signaling pathways activated by ECM stiffness and linked to castration resistance mechanisms in prostate cancer have been recently reviewed [115]. Briefly, they involve AR-centric (for example, the expression of constitutively active AR variants) and AR-independent mechanisms, which might include the activation of FGFR or modulation of the WNT pathway to drive AR-independent growth of prostate cancer.…”

Extracellular Matrix- and Integrin Adhesion Complexes-Related Genes in the Prognosis of Prostate Cancer Patients’ Progression-Free Survival

“…With such an extensive perturbation in the ECM composition, it is hard to speculate which characteristics of the ECM changed. However, it is known from the literature that the tumor ECM in general gains an increase in density and mechanical stiffness [47] due to the changed quantity of ECM structural proteins and the extent of crosslinking.…”

“…As mentioned in the Results Section, with such a comprehensive change in the expression of individual components, it is hard to speculate which of the ECM general characteristics are changed in prostate cancer. However, it is known from the literature that the cancers' ECMs in general gain an increase in density and mechanical stiffness [47].…”