Proteoglycans in the Pathogenesis of Hormone-Dependent Cancers: Mediators and Effectors

Abstract

Hormone-dependent cancers exhibit high morbidity and mortality. In spite of advances in therapy, the treatment of hormone-dependent cancers remains an unmet health need. The tumor microenvironment (TME) exhibits unique characteristics that differ among various tumor types. It is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded and supported by components of the extracellular matrix (ECM). Therefore, the interactions among cancer cells, stromal cells, and components of the ECM determine cancer progression and response to therapy. Proteoglycans (PGs), hybrid molecules consisting of a protein core to which sulfated glycosaminoglycan chains are bound, are significant components of the ECM that are implicated in all phases of tumorigenesis. These molecules, secreted by both the stroma and cancer cells, are crucial signaling mediators that modulate the vital cellular pathways implicated in gene expression, phenotypic versatility, and response to therapy in specific tumor types. A plethora of deregulated signaling pathways contributes to the growth, dissemination, and angiogenesis of hormone-dependent cancers. Specific inputs from the endocrine and immune systems are some of the characteristics of hormone-dependent cancer pathogenesis. Importantly, the mechanisms involved in various aspects of cancer progression are executed in the ECM niche of the TME, and the PG components crucially mediate these processes. Here, we comprehensively discuss the mechanisms through which PGs affect the multifaceted aspects of hormone-dependent cancer development and progression, including cancer metastasis, angiogenesis, immunobiology, autophagy, and response to therapy.

Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy

“…Indeed, the recent advancements in the GAG structure/function relationship have allowed a better appreciation of the GAGs role in tumorigenesis and the utilization of this knowledge for cancer detection, prognosis, and therapy implementation. GAGs are now being employed as biomarkers for disease progression and tumor aggressiveness [ 278 ].They are involved in the tumor immune response, can be used by themselves or in the form of hybrid PGs therapeutic targets, and offer targeted drug delivery [ 1 , 279 ]. As drug carriers, GAGs are characterized by high specificity, multi-functionality, and good biocompatibility, the key to the success of new therapies in oncology [ 279 ].…”

“…The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM) [ 1 ]. The ECM is a significant component of the TME with a vital role in cancer’s pathogenesis [ 2 , 3 ].…”

“…Likewise, GAGs’ interactions with the above, both soluble and insoluble ligands, play a vital role in various diseases, including cancer [ 20 ]. By modulating numerous signaling pathways, GAGs exert distinct effects on cancer cells’ functions, cancer stroma interactions, and cancer-associated inflammation, thus regulating essential processes for tumor progression and metastasis [ 1 , 4 , 6 , 21 ].…”

The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis

“…The TME consists of tumor cells, non-malignant cells, stromal cells, infiltrating immune cells, and blood vessels embedded in the ECM [89,90]. The tumor cells have evolved mechanisms of interaction with the non-malignant components of the TME, which alter this compartment to facilitate tumor progression [91].…”

The bumpy road to achieve herd immunity in COVID-19

“…[74] The factors that influence the immune system are extremely diverse, from lifestyle, diet to chronic inflammation and obesity, from neuroendocrine factors to environmental factors. [75][76][77][78][79][80] Obesity is a factor that drives difficult cases of SARS-Cov2 infection and this is one of the first clinical observation in the current pandemic. A probable explanation is that the enlarged number of adipocytes would contribute to the increased inflammation pattern of the infection.…”