The CEA family comprises 18 genes and 11 pseudogenes located at chromosome 19q13.2 and is divided into two main groups: cell surface anchored CEA-related cell adhesion molecules (CEACAMs) and the secreted pregnancy-specific glycoproteins (PSGs). CEACAMs are highly glycosylated cell surface anchored, intracellular, and intercellular signaling molecules with diverse functions, from cell differentiation and transformation to modulating immune responses associated with infection, inflammation, and cancer. In this review, we explore current knowledge surrounding CEACAM1, CEACAM5, and CEACAM6, highlight their pathological significance in the areas of cancer biology, immunology, and inflammatory disease, and describe the utility of murine models in exploring questions related to these proteins.
Background: Sex differences, microbiome alterations and obesity are prominent factors modulating gastrointestinal (GI) cancers, such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, there is a limited understanding of the interactions between intestinal epithelial and immune cells that participate in the regulation of the microbiome and the prevention or promotion of inflammation and the development of cancer. CEACAM proteins are immune and epithelial cell regulators, and some CEACAMs (CEACAM1, 3, 5, and 6) bind to pathogenic microbes. CEACAMs and mutations of the encoding genes are potential drivers of microbiome changes through altered regulation of host-immune response, through a mechanism that we hypothesize involves TGF-β signaling. We found that genetic alterations in CEACAM-encoding genes correlate with scores of TGF-β pathway activity in GI cancers in The Cancer Genome Atlas (TCGA). Furthermore, nearly 40% of human GI cancers have genetic alterations in components and regulators of the TGF-β pathway. We, therefore, investigated crosstalk between pathogen-binding CEACAM1, the gut microbiome, and the multifunctional intrinsically disordered protein βII-spectrin (SPTBN1), a Smad3 adaptor in driving CRC and liver cancers. Methods: The DNA from fecal samples collected from wild-type mice or TGF-β signaling-deficient mice Smad4+/-Sptbn1+/- were analyzed through shotgun metagenomics sequencing to identify changes in gut microbiota composition. We examined CEACAM expression, changes in the T cell populations, liver inflammation, and cancer in tissues from liver-specific βII-spectrin knockout (LSKO) mice fed a Western diet. Results: Mice heterozygous for the Sptbn1 gene (Sptbn1+/-) combined with heterozygosity of Smad4 (Smad4+/-Sptbn1+/-) spontaneously developed GI cancers, in the C57BL/6J genetic background. These mice exhibit an increased bacterial species associated with CRC in humans (C. septicum) and decreased commensal gut microbes associated with a healthy microbiome (B. vulgatus, P. distasonis). In addition, male Sptbn1+/- mice spontaneously developed HCC and showed reduced regulatory T (Treg) cells, whereas female mice did not, suggesting that βII-spectrin has a role in immune cell homeostasis that may affect tumor suppression. Single cell analyses revealed that Ceacam1 expression decreases in hepatocytes in mice fed a Western diet. CEACAM1 levels are restored to normal in tissues from liver-specific βII-spectrin knockout (LSKO) mice. Furthermore, we observed diet-induced changes in the T cell populations, liver inflammation, and cancer are also blocked in LSKO mice. Conclusion: Our study highlights how two critical pathways, TGF-β signaling and immune mediators CEACAM1 and 5, can drive inflammation and cancer through microbiome alterations with host sex having marked impact on the relevant signaling pathways. Citation Format: Krishanu Bhowmick, Addison Klebanov, Sahara John, Xiaochun Yang, Xiyan Xiang, Anil Vegesna, Kazufumi Ohshiro, James M. Crawford, Nicole Beauchemin, Raja Mazumder, Keith A. Crandall, Lopa Mishra. Impact of sex differences on cross-talk between the gut microbiome, CEACAMs, and TGF-β signaling in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 645.
Background: Non-alcoholic steatohepatitis (NASH) and cirrhosis are major risk factors for hepatocellular carcinoma (HCC), which affects men 2-4 times more than women. In tumors Pyruvate kinase M2 (PKM2), induces aerobic glycolysis (Warburg effect) and proinflammatory and non-apoptotic cell death, ferroptosis. Raised levels of hepatic macrophage PKM2 expression are associated with poor prognosis HCC. We previously found that liver specific TGF-β/SMAD4 knockout mice develop iron deposition and hemochromatosis due to a dramatic loss of hepcidin. Moreover, Smad4+/−Sptbn1+/− mice develop gastrointestinal cancers but only in the presence of an altered microbiome. Recently, we found that liver-specific knockout of a TGF-β/SMAD3/4 adaptor protein, βII-spectrin (LSKO) blocks diet-induced NASH and HCC in mice, as well as in siRNA treated human NASH microfluidic cultures (Sci Transl Med. 2021;13(624): eabk2267). We hypothesized that βII-spectrin modulates PKM2 expression in NASH fatty liver, promoting proinflammatory cytokine release, inflammation and tumorigenesis. In addition, microbiome changes could alter hepcidin function and modulate ferroptosis. Our goal is to understand the molecular mechanism underlying PKM2 driven NASH and HCC. Methods: For our NASH mouse model, we fed SPTBN1Flox (control) and liver-specific βII-spectrin knockout (SPTBN1LSKO) mice a Western diet (WD). Body weight, total cholesterol, and triglyceride concentrations in serum were monitored, and PKM2 expression levels in the liver tissues was analyzed. SPTBN1Flox and SPTBN1LSKO mice were treated with both WD and Diethylnitrosamine (DEN) for HCC, and gut microbiome profiles were performed in these mice. To evaluate PKM2 expression in the NASH-associated HCC mouse model, immunohistochemical labeling was performed on liver tissues of these mice with PKM2-specific antibody. Inflammation, lipidosis and fibrosis were determined with H&E, Oil Red O and Sirius Red staining. Results: We found upregulation of PKM2 expression in NASH and HCC Kupffer cells (WD SPTBN1Flox mice). In contrast, PKM2 expression was markedly reduced in the liver in WD SPTBN1LSKO that blocked NASH and HCC. Interestingly, microbiome profiles were altered and TGF-β/SMAD3-regulated fibrosis as well as expression of inflammatory genes were significantly reduced in LSKO mice, compared to the NASH mice. Conclusions: Our findings suggest that the knockdown of the Smad3/4 adaptor βII-spectrin decreases PKM2 expression in Kupffer cells, thereby suppressing pro-inflammatory cytokine production, blocking NASH-associated HCC. Hepatic macrophages such as Kupffer cells and monocyte-derived macrophages could therefore play a critical role in the ferroptosis-mediated protumor immune microenvironment. In addition, our work provides new insight into potential mechanism for two disorders that affect males more than females, hemochromatosis and HCC. Citation Format: Kazufumi Ohshiro, Krishanu Bhowmick, Xiaochun Yang, Addison Klebanov, Sahara John, Dillon Voss, Adrian Krainer, Lopa Mishra. PKM2 Modulates hepatic macrophage regulation of NASH, ferroptosis and HCC through TGF-β signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4854.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.