Abstract
Hyaluronan (HA) cross-linking is a conformational state of HA, a covalent complex between HA and heavy chains (HCs) from inter-α-trypsin inhibitor (I-α-I) mediated by tumor necrosis factor-induced protein 6 (TSG6). Cross-linked HA has been identified as a protective factor in physiological and inflammatory conditions. However, the state of HA cross-linking in tumor microenvironment has not been fully elucidated. As a major constituent of the extracellular matrix (ECM), HA is mainly synthesized by cancer-associated fibroblasts (CAFs). Our study aimed to clarify the role of HA cross-linking in breast cancer malignancy. Compared to normal mammary gland tissues, cross-linked HA levels were significantly decreased in breast cancer and associated with tumor malignancy. When NFbs were activated into CAFs, the levels of cross-linked HA and TSG6 were both suppressed. Through upregulating TSG6, CAFs restored the high level of cross-linked HA and significantly inhibited breast cancer malignancy, whereas NFbs promoted the malignancy when the cross-linked HA level was reduced. Furthermore, the inhibitory role of HA cross-linking in tumor malignancy was directly verified using the synthesized HA-HC complex. Collectively, our study found that the deficiency of cross-linked HA induced breast cancer malignancy in a CAF-dependent manner, suggesting that recovering HA cross-linking may be a potential therapeutic strategy.
Highlights
During malignancy, tumor cells must establish a favorable microenvironment or niche that will sustain their growth
The co-localization of HA and inter-α-trypsin inhibitor (I-α-I) heavy chains (HCs) is usually used to determine the existence of HA crosslinking in tissues[15,16,36]
HA was co-localized with I-α-I HC1 or I-α-I HC2, suggesting that HA was covalently modified with HCs of I-α-I to form HA-HC complexes
Summary
Tumor cells must establish a favorable microenvironment or niche that will sustain their growth. Cancer-associated fibroblasts (CAFs) are the most abundant mesenchymal cells in the tumor microenvironment[1]. CAFs promote tumor malignancy and serve as a marker for cancer diagnosis, treatment, and prognosis[2,3,4]. When normal fibroblasts (NFbs) are activated into CAFs, the cytokines secreted and extracellular matrix (ECM) around were altered dramatically[5]. The pathological remodeling of ECM affects the proliferation, survival, and metastasis of tumor cells[6,7]. Hyaluronan (HA), a linear polysaccharide composed of repeating disaccharide units of D-glucuronic acid and
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