Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer? - PubMed (original) (raw)

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Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer?

Li Yang et al. Cancer Res. 2008.

Abstract

Therapies targeting transforming growth factor beta (TGFbeta) signaling using neutralizing antibodies and small molecular inhibitors are in multiple clinical trails. However, TGFbeta is known to work as both a tumor suppressor and a tumor promoter, and current knowledge does not provide sufficient information on what factors mediate this switch in function and when this switch occurs. Recent advances in multiple disciplines suggest that immune cells from the tumor host may provide the answer.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1

Figure 1

The TGFβ ligands signal through the type I and type II TGFβ receptors. Canonical signaling proceeds with phosphorylation of Smad2 and Smad3, which then combine with Smad4 to enter the nucleus to mediate growth inhibition. Smad7 is a negative mediator in this process. In addition, TGFβ binding to its receptors activates many noncanonical signaling pathways and regulates tumor cell migration and metastasis.

Figure 2

Figure 2

How TGFβ signaling switches from being tumor suppressive to tumor promoting is unknown. Host-derived immature myeloid Gr-1+CD11b+ cells are recruited into the tumor microenvironment with deletion of the type II TGFβ receptor gene in mammary carcinomas through CXCL5/CXCR2 and SDF-1/CXCR4. In addition, Gr-1+CD11b+ cells express high levels of MMPs and TGFβ1, which promote tumor invasion and immune suppression. The effects of Gr-1+CD11b+ cells on the tumor microenvironment and host immunosurveillance constitute a tumor-promoting mechanism of TGFβ signaling.

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