Glycoprotein asporin as a novel player in tumour microenvironment and cancer progression

Abstract

Background. Small leucine rich proteoglycans (SLRPs), major non-collagen components of the extracellular matrix (ECM), have multiple biological roles with diverse effects. Asporin, a member of the SLRPs class I, competes with other molecules in binding to collagen and affects its mineralization. Its role in cancer is only now being elucidated. Methods. The PubMed online database was used to search relevant reviews and original articles. Furthermore, altered asporin expression was analysed in publicly available genome-wide expression data at the Gene Expression Omnibus database. Results. Polymorphisms in the N-terminal polyaspartate domain, which binds calcium, are associated with osteoarthritis and prostate cancer. Asporin also promotes the progression of scirrhous gastric cancer where it is required for coordinated invasion by cancer associated fibroblasts and cancer cells. Besides the enhanced expression of asporin observed in multiple cancer types, such as breast, prostate, gastric, pancreas and colon cancer, tumour suppressive effects of asporin were described in triple-negative breast cancer. We also discuss a number of factors modulating asporin expression in different cell types relevant for alterations toing the tumour microenvironment. Conclusion. The apparent contradicting tumour promoting and suppressive effects of asporin require further investigation. Deciphering the role of asporin and other SLRPs in tumour-stroma interactions is needed for a better understanding of cancer progression and potentially also for novel tumour microenvironment based therapies.

Cytoplasmic Asporin promotes cell migration by regulating TGF-β/Smad2/3 pathway and indicates a poor prognosis in colorectal cancer

“…Our previous IHC results indicated that ASPN was not only located in the extracellular matrix as most studies reported 9 , but also localized in cytoplasm, and even nucleus. To confirm this phenomenon and provide more clues to uncover related mechanism, we performed immunofluorescence assays and revealed that ASPN co-localized with p-Smad2/3 in the nucleus in both HCT-8 and RKO (Fig.…”

“…Asporin (ASPN), firstly identified in 2001, is a member of small leucine-rich proteoglycan (SLRP) family 9 . Nevertheless, ASPN is distinct from other class 1 SLRP family members because of its unique aspartate residues named the D-repeat 10 .…”

“…Most studies of ASPN on cancers focused on its function as an extracellular matrix component, which was secreted by cancer-associated fibroblasts (CAFs) and then activated or suppressed the receptors located on cancer cell membrane 9 . Subcellular localization of ASPN in the cytoplasm, even in the nucleus, was also observed in many other studies 15,25 , but its exact biological function inside cancer cells was totally unknown.…”

Proteomic profiling identifies markers for inflammation-related tumor–fibroblast interaction

“…TGFβ or stiff matrix. This was not observed in our tumor tissues, which can be regarded as an additional marker of inflammation, as production of ASPN and DCN is suppressed by IL1β [ 73 ] and low abundance of these markers was also observed in triple-negative inflammatory breast cancer CAFs [ 51 ].…”

Targeting nuclear receptors in cancer-associated fibroblasts as concurrent therapy to inhibit development of chemoresistant tumors

“…Hence, CAFs create a microenvironment that promotes proliferation, invasiveness, oxidative stress, aberrant metabolism, immune evasion and therapy resistance of tumors. Although CAFs have been well characterized by their expression of alpha-smooth muscle actin, 10 fibroblast (FIB) activation protein, 11 platelet-derived growth factor receptors, 12 asporin 13 and collagen 11α1, 14 the underlying transcriptional programs enabling the pro-oncogenic functions of CAFs remain poorly understood. Moreover, whereas transcription factor signaling nodes control many cellular behaviors, most transcription factors cannot be directly modulated by chemical drugs, and are considered poor pharmacological targets.…”