Abstract
The tumor microenvironment evolves during malignant progression, with major changes in nonmalignant cells, cytokine networks, and the extracellular matrix (ECM). In this study, we aimed to understand how the ECM changes during neoplastic transformation of serous tubal intraepithelial carcinoma lesions (STIC) into high-grade serous ovarian cancers (HGSOC). Analysis of the mechanical properties of human fallopian tubes (FT) and ovaries revealed that normal FT and fimbria had a lower tissue modulus, a measure of stiffness, than normal or diseased ovaries. Proteomic analysis of the matrisome fraction between FT, fimbria, and ovaries showed significant differences in the ECM protein TGF beta induced (TGFBI, also known as βig-h3). STIC lesions in the fimbria expressed high levels of TGFBI, which was predominantly produced by CD163-positive macrophages proximal to STIC epithelial cells. In vitro stimulation of macrophages with TGFβ and IL4 induced secretion of TGFBI, whereas IFNγ/LPS downregulated macrophage TGFBI expression. Immortalized FT secretory epithelial cells carrying clinically relevant TP53 mutations stimulated macrophages to secrete TGFBI and upregulated integrin αvβ3, a putative TGFBI receptor. Transcriptomic HGSOC datasets showed a significant correlation between TGFBI expression and alternatively activated macrophage signatures. Fibroblasts in HGSOC metastases expressed TGFBI and stimulated macrophage TGFBI production in vitro. Treatment of orthotopic mouse HGSOC tumors with an anti-TGFBI antibody reduced peritoneal tumor size, increased tumor monocytes, and activated β3-expressing unconventional T cells. In conclusion, TGFBI may favor an immunosuppressive microenvironment in STICs that persists in advanced HGSOC. Furthermore, TGFBI may be an effector of the tumor-promoting actions of TGFβ and a potential therapeutic target. SIGNIFICANCE: Analysis of ECM changes during neoplastic transformation reveals a role for TGFBI secreted by macrophages in immunosuppression in early ovarian cancer.
Highlights
There are increasingly compelling data to show that fallopian tube secretory epithelial (FTSE) cells are the progenitors of many highgrade serous ovarian carcinomas (HGSOC; refs. 1–8)
TGFb signaling in the FB may prime macrophages to secrete TGFBI, which is an effector of an immunosuppressive microenvironment promoting transformed FTSE cell growth and serous tubal intraepithelial carcinoma lesions (STIC) development
We have provided evidence that the extracellular matrix (ECM) protein TGFBI contributes to an immune-suppressive microenvironment in HGSOC
Summary
There are increasingly compelling data to show that fallopian tube secretory epithelial (FTSE) cells are the progenitors of many highgrade serous ovarian carcinomas (HGSOC; refs. 1–8). Tumor matrix is primarily laid down by fibroblasts but immune cells, in particular macrophages, are associated with physiologic and abnormal ECM expression [14,15,16]. Whereas metastasizing HGSOC cells attach and infiltrate omental tissue that has relatively low endogenous ECM levels, STIC lesions and early HGSOCs in the ovary are developing in a stroma-rich microenvironment. It is not clear why and how transformed FTSE cells spread from the fimbrial end of the FT and adhere to the ovarian surface. We found that tumor-associated macrophages (TAM) were the predominant cell type secreting TGFBI in STIC lesions. In silico and mouse model experiments using our recently developed orthotopic HGSOC models [17] led us to conclude that TGFBI is an important component of tumor microenvironments at different sites and stages of HGSOC and that it may contribute to immunosuppression and disease progression
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
