Dataset Information

Mesenchymal stem cells can prevent or promote the progression of colon cancer based on their timing of administration.

ABSTRACT:

Background

Mesenchymal stem cell (MSC) therapy has been shown to have some therapeutic effects in rodent models and patients with IBD; however, its role in colon tumor models is controversial. In this study, the potential role and mechanisms of bone marrow-derived MSCs (BM-MSCs) in colitis-associated colon cancer (CAC) were investigated.

Methods

The CAC mouse model was established with azoxymethane (AOM) and dextran sulfate sodium (DSS). The mice were administered an intraperitoneal injection of MSCs once weekly for different periods. The progression of CAC and the cytokine expression in tissues was assessed. Immunofluorescence staining was used to detect MSCs localization. Levels of immune cells in the spleen and lamina propria of the colon were detected using flow cytometry. A co-culture of MSCs and naïve T cells was performed to determine the effect of MSCs on naïve T cell differentiation.

Results

Early administration of MSCs inhibited the occurrence of CAC, while late administration promoted the progression of CAC. The inhibitory effect of early injection in mice was characterized by the expression of inflammatory cytokines in colon tissue was decreased, and induction of T regulatory cells (Tregs) infiltration via TGF-β. The promotive effect of late injection was characterized by a shift of T helper (Th) 1/Th2 immune balance toward a Th2 phenotype through IL-4 secretion. IL-12 can reverse this shift to Th2 accumulation in mice.

Conclusion

MSCs can curb the progression of colon cancer by inducing Treg accumulation via TGF-β at the early stage of inflammatory transformation but promote the progression of colon cancer by inducing a shift in Th1/Th2 immune balance to Th2 through IL-4 secretion at the late stage. And the immune balance of Th1/Th2 influenced by MSCs could be reversed by IL-12.

SUBMITTER: Hu W

PROVIDER: S-EPMC10045613 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Mesenchymal stem cells can prevent or promote the progression of colon cancer based on their timing of administration.

Hu Weiqian W Wang Weijun W Jiang Xin X Wang Zeyu Z Lin Rong R

Journal of translational medicine 20230328 1

<h4>Background</h4>Mesenchymal stem cell (MSC) therapy has been shown to have some therapeutic effects in rodent models and patients with IBD; however, its role in colon tumor models is controversial. In this study, the potential role and mechanisms of bone marrow-derived MSCs (BM-MSCs) in colitis-associated colon cancer (CAC) were investigated.<h4>Methods</h4>The CAC mouse model was established with azoxymethane (AOM) and dextran sulfate sodium (DSS). The mice were administered an intraperitone ...[more]

PMID: 36978120

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Project description:There is still a lively debate about whether mesenchymal stem cells (MSCs) promote or suppress antitumor immune response. Although several possible explanations have been proposed, including different numbers of injected and engrafted MSCs, heterogeneity in phenotype, and function of tumor cells, the exact molecular mechanisms responsible for opposite effects of MSCs in modulation of antitumor immunity are still unknown. Herewith, we used a B16F10 murine melanoma model to investigate whether timing of MSC administration in tumor-bearing mice was crucially important for their effects on antitumor immunity. MSCs, intravenously injected 24?h after melanoma induction (B16F10+MSC1d-treated mice), significantly enhanced natural killer (NK) and T cell-driven antitumor immunity, suppressed tumor growth, and improved survival of melanoma-bearing animals. Significantly higher plasma levels of antitumorigenic cytokines (TNF-? and IFN-?), remarkably lower plasma levels of immunosuppressive cytokines (TGF-? and IL-10), and a significantly higher number of tumor-infiltrating, IFN-?-producing, FasL- and granzyme B-expressing NK cells, IL-17-producing CD4+Th17 cells, IFN-?- and TNF-?-producing CD4+Th1 cells, and CD8+cytotoxic T lymphocytes (CTLs) were observed in B16F10+MSC1d-treated mice. On the contrary, MSCs, injected 14 days after melanoma induction (B16F10+MSC14d-treated mice), promoted tumor growth by suppressing antigen-presenting properties of tumor-infiltrating dendritic cells (DCs) and macrophages and by reducing tumoricidal capacity of NK cells and T lymphocytes. Significantly higher plasma levels of TGF-? and IL-10, remarkably lower plasma levels of TNF-? and IFN-?, and significantly reduced number of tumor-infiltrating, I-A-expressing, and IL-12-producing macrophages, CD80- and I-A-expressing DCs, granzyme B-expressing CTLs and NK cells, IFN-?- and IL-17-producing CTLs, CD4+Th1, and Th17 cells were observed in B16F10+MSC14d-treated animals. In summing up, the timing of MSC administration into the tumor microenvironment was crucially important for MSC-dependent modulation of antimelanoma immunity. MSCs transplanted during the initial phase of melanoma growth exerted tumor-suppressive effect, while MSCs injected during the progressive stage of melanoma development suppressed antitumor immunity and enhanced tumor expansion.

Project description:BackgroundTumor microenvironment (TME) plays a very important role in cancer progression. The mesenchymal stem cells (MSC), a major compartment of TME, have been shown to promote hepatocellular carcinoma (HCC) progression and metastasis. As hypoxia is a common feature of TME, it is essential to investigate the effects of hypoxia on MSC during HCC progression.MethodsThe effects of hypoxia on MSC mediated cell proliferation and HCC progression were measured by cell counting kit-8 (CCK-8) assay, Edu incorporation assay and xenograft model. The role of cyclooxygenase 2 (COX2) during this process was evaluated via lentivirus mediated COX2 knockdown in MSC. We also assessed the levels and localization of yes-associated protein (YAP) in HCC cells by immunofluorescence, western blot and real-time PCR, in order to detect the alterations of Hippo pathway. The changes in lipogenesis was examined by triacylglycerol (TG) levels, BODIPY staining of neutral lipid, and lipogenic enzyme levels. The alterations in AKT/mTOR/SREBP1 pathway were measured by western blot. In addition, to evaluate the role of prostaglandin E receptor 4 (EP4) in MSC mediated cell proliferation under hypoxia, we manipulated the levels of EP4 in HCC cells via small interfering RNA (siRNA), EP4 antagonist or agonist.ResultsWe found that MSC under hypoxia condition (hypo-MSC) could promote proliferation of HCC cell lines and tumor growth in xenograft model. Hypoxia increased COX2 expression in MSC and promoted the secretion of prostaglandin E2 (PGE2), which then activated YAP in HCC cells and led to increased cell proliferation. Meanwhile, YAP activation enhanced lipogenesis in HCC cell lines by upregulating AKT/mTOR/SREBP1 pathway. Knockdown or overexpression of YAP significantly decreased or increased lipogenesis. Finally, EP4 was found to mediate the effects of hypo-MSC on YAP activation and lipogenesis of HCC cells.ConclusionsHypo-MSC can promote HCC progression by activating YAP and the YAP mediated lipogenesis through COX2/PGE2/EP4 axis. The communication between MSC and cancer cells may be a potential therapeutic target for inhibiting cancer growth.

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Dataset Information

Mesenchymal stem cells can prevent or promote the progression of colon cancer based on their timing of administration.

Background

Methods

Results

Conclusion

Publications

Mesenchymal stem cells can prevent or promote the progression of colon cancer based on their timing of administration.

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