Novel mechanism of tumorigenesis: Increased transforming growth factor‐β1 suppresses the expression of connexin 43 in BALB/cJ mice after implantation of poly‐L‐lactic acid

Abstract

Poly-L-lactic acid (PLLA) is a widely used promising material for surgical implants such as tissue-engineered scaffolds. In this study, we aimed to determine the in vivo effect of PLLA plates on the cellular function of subcutaneous tissue in the two mouse strains, BALB/cJ and SJL/J, higher and lower tumorigenic strains, respectively. Gap-junctional intercellular communication (GJIC) and the expression of connexin 43 (Cx43) protein were significantly suppressed, whereas the secretion of transforming growth factor-beta 1 (TGF-beta 1) level was significantly increased in PLLA-implanted BALB/cJ mice compared with BALB/cJ controls. However, no significant difference in TGF-beta 1 secretion was observed between the SJL/J-implanted and SJL/J control mice. We found for the first time that a significant difference was observed between the two strains; thus, the PLLA increased the secretion of TGF-beta 1 and suppressed the mRNA expression of Cx43 at the earlier stage after implantation into the higher-tumorigenic strain, BALB/cJ mice. This novel mechanism might have a vital role in the inhibition of GJIC and promote the tumorigenesis in BALB/cJ mice.

Effects of cytokines on microglial phenotypes and astroglial coupling in an inflammatory coculture model

“…This increased expression of TGF-b1 is discussed to be one mechanism by which corticosteroids and IFN-b1b mediate their immunosuppressive action in the treatment of MS. Less is known about the effect of antiinflammatory treatment on Cx43 expression but it has been shown that TGF-b1 raises gap-junctional communication and Cx43 expression in astrocytes and endothelial cells (Larson et al, 1997;Robe et al, 2000). In contrast, suppressed junctional communication and expression of Cx43 mediate increased secretion of TGF-b1 in tumorigenic mouse strains (Ahmed and Tsuchiya, 2004). Another possible mechanism is the enhanced production of the immunosuppressive cytokine IL-10 by monocytes from MS patients treated with IFN-b (Porrini et al, 1995).…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…Lactic acid was shown to induce both transcription and protein secretion of TGFβ2 in glioma cells [32] and to induce TGFβ1 production in in vivo model [33]. More recently, we found that an acidic microenvironment is able to promote TGFβ secretion and signaling in mesenchymal stem cells (MSC), driving the progression to malignancy in a melanoma cell system [34] and suggesting that acidity is a strong inducer of TGFβ family members.…”

Targeting the Metabolic Reprogramming That Controls Epithelial-to-Mesenchymal Transition in Aggressive Tumors

“…According to the pivotal role exerted by lactate in the promotion of the metastatic process, lactate can induce the upregulation of TGF-β2 expression (54), which in turn induces a mesenchymal pro-migratory phenotype of glioblastoma cells and promotes MMP-2 activation, ECM remodeling, and metastasis formation (55). It has also been reported that lactate is able to induce the production of TGF-β1 in vivo (56). In keeping, it has been shown that lactate administration promotes in vitro migration of human breast carcinoma cells as well as experimental lung metastases in mice intraperitoneally injected with lactate (57).…”