TREM2 Acts as a Tumor Suppressor in Colorectal Carcinoma through Wnt1/β-catenin and Erk Signaling

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad‐spectrum anticancer drugs. Cyclin‐dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA‐approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid‐beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD‐omics and preclinical animal models provided data supporting the long‐standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re‐entry, leading to the “amyloid‐beta accumulation cycle,” may be a prerequisite for amyloid‐beta accumulation and AD pathology development; (b) AD‐associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the “amyloid‐beta accumulation cycle is an AD drug target” concept is proven, repurposing of cancer drugs may emerge as a new, fast‐track approach for AD management in the clinic setting.

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“…Acts as a tumor suppressor via Wnt1/β-catenin and Erk signaling in colorectal carcinoma (Kim et al, (2019)…”

Section: Cd2-associated Proteinmentioning

confidence: 99%

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

et al. 2020

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“…Aside from HCC, TREM2 has also been studied in many other tumors, such as colorectal carcinoma, lung cancer, and glioma [124][125][126][127][128]. However, it remains to be explored whether the mechanism of TREM2 in liver tumors and other tumors is consistent.…”

Section: Roles Of Trem In Liver Tumorigenesismentioning

confidence: 99%

Function of TREM1 and TREM2 in Liver-Related Diseases

Sun

Feng

Tang

2020

Cells

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TREM1 and TREM2 are members of the triggering receptors expressed on myeloid cells (TREM) family. Both TREM1 and TREM2 are immunoglobulin superfamily receptors. Their main function is to identify foreign antigens and toxic substances, thereby adjusting the inflammatory response. In the liver, TREM1 and TREM2 are expressed on non-parenchymal cells, such as liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells, and cells which infiltrate the liver in response to injury including monocyte-derived macrophages and neutrophils. The function of TREM1 and TREM2 in inflammatory response depends on Toll-like receptor 4. TREM1 mainly augments inflammation during acute inflammation, while TREM2 mainly inhibits chronic inflammation to protect the liver from pathological changes. Chronic inflammation often induces metabolic abnormalities, fibrosis, and tumorigenesis. The above physiological changes lead to liver-related diseases, such as liver injury, nonalcoholic steatohepatitis, hepatic fibrosis, and hepatocellular carcinoma. Here, we review the function of TREM1 and TREM2 in different liver diseases based on inflammation, providing a more comprehensive perspective for the treatment of liver-related diseases.

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“…TREMs have emerged as critical immune regulators that modulate in ammatory responses in macrophages, glial cells, and DCs [41,[43][44][45]. Recently, several groups reported TREM2 as a novel tumor suppressor in colorectal and hepatocellular carcinoma [40,46]. However, the function of TREM2 in NK cells has not yet been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…However, autologous NK therapy for patients with cancer has several limitations [47]. Ex vivo NK cell expansion is di cult, and IL-2 treatment for NK cell activation causes severe side effects [40]. Therefore, it is necessary to nd new ways to alter NK cell function, which is modulated by activating receptors that have binding motifs for the associated adaptor protein DAP12.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, TREM2 expression has also been identi ed as a risk factor for late-onset dementia and Alzheimer's disease [31], [34][35][36][37][38][39]. Furthermore, TREM2 acts as a tumor suppressor in colorectal carcinoma and hepatocellular carcinoma through WNT1/β-catenin and extracellular signal-regulated kinase signaling or PI3K/AKT/β-catenin signaling [40,41]. Nonetheless, although the structure of TREM2 is similar to that of NK cell receptors, its effect on NK cells remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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TREM2 Promotes Natural Killer Cell Development in CD3-CD122+NK1.1+ pNK Cells

Lee

et al. 2020

Preprint

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Background: Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells.Results: Here, we demonstrated for the first time that CD3-CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice.Conclusions: Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

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TREM2 Acts as a Tumor Suppressor in Colorectal Carcinoma through Wnt1/β-catenin and Erk Signaling

Cited by 31 publications

References 40 publications

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

Function of TREM1 and TREM2 in Liver-Related Diseases

TREM2 Promotes Natural Killer Cell Development in CD3-CD122+NK1.1+ pNK Cells

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