Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C

Abstract

A central and unique aspect of high-grade serous ovarian carcinoma (HGSC) is the extensive transcoelomic spreading of tumor cell via the peritoneal fluid or malignant ascites. We and others identified tumor-associated macrophages (TAM) in the ascites as promoters of metastasis-associated processes like extracellular matrix (ECM) remodeling, tumor cell migration, adhesion, and invasion. The precise mechanisms and mediators involved in these functions of TAM are, however, largely unknown. We observed that HGSC migration is promoted by soluble mediators from ascites-derived TAM, which can be emulated by conditioned medium from monocyte-derived macrophages (MDM) differentiated in ascites to TAM-like asc-MDM. A similar effect was observed with IL-10-induced alternatively activated m2c-MDM but not with LPS/IFNγ-induced inflammatory m1-MDM. These observations provided the basis for deconvolution of the complex TAM secretome by performing comparative secretome analysis of matched triplets of different MDM phenotypes with different pro-migratory properties (asc-MDM, m2c-MDM, m1-MDM). Mass spectrometric analysis identified an overlapping set of nine proteins secreted by both asc-MDM and m2c-MDM, but not by m1-MDM. Of these, three proteins, i.e., transforming growth factor beta-induced (TGFBI) protein, tenascin C (TNC), and fibronectin (FN1), have been associated with migration-related functions. Intriguingly, increased ascites concentrations of TGFBI, TNC, and fibronectin were associated with short progression-free survival. Furthermore, transcriptome and secretome analyses point to TAM as major producers of these proteins, further supporting an essential role for TAM in promoting HGSC progression. Consistent with this hypothesis, we were able to demonstrate that the migration-inducing potential of asc-MDM and m2c-MDM secretomes is inhibited, at least partially, by neutralizing antibodies against TGFBI and TNC or siRNA-mediated silencing of TGFBI expression. In conclusion, the present study provides the first experimental evidence that TAM-derived TGFBI and TNC in ascites promote HGSC progression.

Deep learning on image-omics data in identifying prognostic immune biomarkers for ovarian cancer

“…CAFs have been shown to facilitate cancer progression by supporting tumor cell growth, extracellular matrix remodeling, angiogenesis, and formation of an immunosuppressive microenviroment 71 . These results are supported by our research showing that CAF subtypes CD73_1 and CD73_2 express genes, such as ANGPTL2, TNC, TGFB1, FN1, BMPR1B, and LRRC32, that have been shown to promote tumor progression, angiogenesis, and extracellular matrix remodeling 45,46,52,55,56,75,76 . Some of these genes, including TGFB1, BMPR1B, and LRRC32, have been shown to modulate TGF-β signaling, which suppresses in ltration of anticancer immune cells such as cytotoxic T cells and natural killer cells and promotes the function of pro-cancer immune cells, such as regulatory T cells and M2 macrophages, in the tumor microenvironment 45,77,78 , leading to poor patient survival rates.…”

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

“…The biological behavior of ovarian carcinoma differs from other tumors by the pattern of hematogenous metastasis through transcoelomic dissemination of tumor cells via the peritoneal fluid (202,203). In ascite, cancer cells detached from the primary tumor obtain EMT phenotype, form multicellular spheroids and attach preferentially on the abdominal peritoneum or omentum through a passive mechanism, carried by the physiological movement of peritoneal fluid (203).…”

“…In ovarian cancer TAMs have a clinical significance not only by infiltrating tumor mass but also by the interacting closely with cancer cells in ascites. Ascite, which is a hallmark of OC, contains a large number of components of unique peritoneal TME, including tumor spheroids and immune cells, such as TAMs and T cells (201,202). Experimental mouse models have demonstrated that TAMs constitute a major cell fraction in ascites that support the survival of cancer cells and promote cancer progression, chemoresistance, and immunosuppression (202,204,(221)(222)(223).…”

Comprehensive analysis of DNA methylation and gene expression profiles in rectal cancer

“…TGFBI (transforming growth factor betainduced) is an extracellular secreted matrix protein that plays pivotal roles in cell adhesion by binding to integrin at the C-terminus [41] . Steitz et al [42] found that TGFBI could promote ovarian cancer cell migration and was associated with short progression-free survival. TGFBI was also identi ed to be a hub gene strongly associated with oral squamous cell carcinoma and to be able to promote tumor metastasis [43] .…”