Reduced hyaluronan cross-linking induces breast cancer malignancy in a CAF-dependent manner

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.

Cancer‐associated fibroblasts in breast cancer: Challenges and opportunities

“…As a major component of the ECM, hyaluronan (HA) is mainly generated by CAFs and is associated with breast cancer malignancy [351,352]. Pegvorhyaluronidase alfa (PEGPH20), a hyaluronidase, remodeled the TME by degrading HA, increasing the exposure of tumor cells to drugs and augmenting drug efficacy [353].…”

Hyaluronan as “Agent Smith” in cancer extracellular matrix pathobiology: Regulatory roles in immune response, cancer progression and targeting

“…Upregulation of TSG‐6 expression restored HA cross‐linking in CAFs resulting in significant suppression of breast cancer malignancy in vitro and in vivo. This data indicates that cross‐linked HA deficiency within TME was CAF dependent, suggesting that restoring HA cross‐linking could be a potential strategy for breast cancer therapy 46 …”

“…45 Another study highlighted the importance of HA cross-linking in breast cancer. 46 HA crosslinked into stable structures by the interaction with a group of HAbinding proteins, known as hyaladherins. Tumor necrosis factor stimulated gene 6 (TSG-6) is a hyaladherin that catalyzes the transfer of heavy chains from inter-ainhibitor to HA, resulting in inhibition of HYALs, preventing HA degradation and contributing in the structural integrity of ECM.…”

“…This data indicates that cross-linked HA deficiency within TME was CAF dependent, suggesting that restoring HA cross-linking could be a potential strategy for breast cancer therapy. 46 Several studies have also reported recruitment of myeloid cells by inflammatory chemokines and cytokines secreted by both stromal as well as malignant cells. These tumor-recruited myeloid cells have been shown to exert tumor-promoting effects via numerous ways.…”

“…Another study highlighted the importance of HA cross‐linking in breast cancer 46 . HA crosslinked into stable structures by the interaction with a group of HA‐binding proteins, known as hyaladherins.…”