The Landscape of Small Leucine-Rich Proteoglycan Impact on Cancer Pathogenesis with a Focus on Biglycan and Lumican

Abstract

Cancer development is a multifactorial procedure that involves changes in the cell microenvironment and specific modulations in cell functions. A tumor microenvironment contains tumor cells, non-malignant cells, blood vessels, cells of the immune system, stromal cells, and the extracellular matrix (ECM). The small leucine-rich proteoglycans (SLRPs) are a family of nineteen proteoglycans, which are ubiquitously expressed among mammalian tissues and especially abundant in the ECM. SLRPs are divided into five canonical classes (classes I-III, containing fourteen members) and non-canonical classes (classes IV-V, including five members) based on their amino-acid structural sequence, chromosomal organization, and functional properties. Variations in both the protein core structure and glycosylation status lead to SLRP-specific interactions with cell membrane receptors, cytokines, growth factors, and structural ECM molecules. SLRPs have been implicated in the regulation of cancer growth, motility, and invasion, as well as in cancer-associated inflammation and autophagy, highlighting their crucial role in the processes of carcinogenesis. Except for the class I SLRP decorin, to which an anti-tumorigenic role has been attributed, other SLPRs' roles have not been fully clarified. This review will focus on the functions of the class I and II SLRP members biglycan and lumican, which are correlated to various aspects of cancer development.

Keywords: biglycan; cancer; cancer invasion; cancer-associated inflammation; extracelllar matrix; lumican; small-leucine rich proteoglycans (SLRPs).

Figure 1

The roles of biglycan in gastric tumor carcinogenesis. (A) Gastric cancer cell-derived biglycan enhances the transformation of mesenchymal cells into CAF-like cells, which activates TLR signaling. In turn, CAF-like cells secrete fibroblast activation protein (FAP), promoting gastric cancer migration, invasion, and EMT. FAP initiates the JAK2/STAT3 signaling pathway in gastric cancer cells, increasing their biglycan expression. (B) Biglycan stimulates gastric cancer cell invasion and metastasis by activating FAK signaling via specific phosphorylation at Tyr576/577, Tyr925, and Tyr397. (C) Biglycan decreases PARP1 levels and caspase-3 cleavage with a concomitant upregulation of mesenchymal markers. (D) The SEMA3B-AS1/HMGB1/FBXW7 signaling axis is downregulated in gastric cancer cells, which facilitates the peritoneal metastasis of gastric cancer by decreasing biglycan protein ubiquitination and concomitant degradation, leading to higher biglycan levels.

Figure 2

Biglycan upregulates osteosarcoma cell growth. (A) Biglycan binds to IGF-IR, enhancing its activation, subsequent sumoylation, and translocation to the nucleus. Nuclear IGF-IR regulates the transcription of target genes, including Cyclin D1, thus increasing osteosarcoma cell growth. (B) Upon biglycan binding to IGF-IR and its phosphorylation, downstream RAS/RAF/Erk_1/2 signaling cascade is activated, resulting in transcriptional regulation that enhances osteosarcoma cell growth. (C) Biglycan binds to LRP6 and disrupts the formation of the β-catenin degradation complex, resulting in β-catenin nuclear translocation and transcriptional regulation that promotes osteosarcoma cell growth. (D) β-catenin co-localizes with IGF-IR, prolonging its activation and downstream signaling, which is correlated with increased osteosarcoma cell proliferation. (E) Activated Erk1/2 and β-catenin co-localize to facilitate β-catenin intracellular pool.

Figure 3

The effects of biglycan on tumor-associated angiogenesis. Biglycan secreted by cancer cells or CAFs can take the following actions: (A) modulate TNF-α/angiopietin-1 signaling to facilitate angiogenesis; (B) activate Erk1/2-dependent VEGF secretion, resulting in increased angiogenesis; (C) facilitate the interaction between the biglycan promoter (BGN-pro) and HIF-1, resulting in increased VEGF production; (D) biglycan, by binding to TLR2/4/CD14, enhances inflammation-dependent angiogenesis; (E) ROS inhibits the expression of a negative regulator of biglycan transcription NRF2 in TECs, the increased of which expression enhances their pro-angiogenic phenotype.