Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

Abstract

Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer.

Biglycan enhances the ability of migration and invasion in endometrial cancer

“…However, BGN stimulated the migration of the lung fibroblasts cells by activating the signal pathway of RhoA and Rac1 [32]. It suggests that BGN enhanced the cell migration and development of metastasis through the BGN-FAK-paxillin-Rac1-signaling as paxillin phosphorylation is involved in Rac activation [33]. In the future, antiadhesive effects of BGN may play a significant role in the mechanisms of tumor metastasis [34].…”

Decorin as a multivalent therapeutic agent against cancer

“…They reflect the multifactorial propensity of the matrix, and subsume crucial roles over a spectrum of homeostatic and pathological conditions [11]. This 18-member strong gene family is proving critical for restraining the development, progression, and dissemination of various solid tumors [12-14]. Decorin, the archetypical SLRP, harbors a single, covalently-attached N-terminal glycosaminoglycan (GAG) chain consisting of either dermatan or chondroitin sulfate, twelve leucine-rich tandem repeats (LRR), and a class-specific C-terminal Ear domain [15].…”

“…Despite a large literature describing decorin as an oncosuppressive proteoglycan [12,13,31,54], there are still several incongruencies that need to be addressed. In particular, the absence of decorin in the breast tumor stroma has been established as an important clinical prognosticator of invasive and metastatic breast cancer [10,55-57] as well as in soft tumors [58].…”

Proteoglycans in normal physiology and carcinogenesis

“…Состав и структура ГСПГ подвергаются значитель-ным изменениям в опухолях яичников и молочной железы человека [46,47]; экспрессия синдекана 1, де-корина и люмикана значительно изменяется в опухолях молочной железы [48], глипиканы вовлечены в процесс канцерогенеза в тканях легкого [49] и поджелудочной железы [50]; синдеканы участвуют в патогенезе лимфомы Ходжкина [51]; экспрессия перлекана и серглицина значительно снижается в клетках лимфомы Беркитта [52]; уровень экспрессии коллагена 18 ассоциируется с прогрессированием и прогнозом гепатоцеллюлярной карциномы [53], а в опухолях прямой кишки проис-ходит одновременное снижение уровней экспрессии декорина и перлекана (в 2 раза) и повышение экспрес-сии бигликана и версикана (в 6 и 3 раза соответственно) [54]. ПГ глипиканы, агрин, версикан и декорин при-нимают активное участие в развитии злокачественных [55].…”