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An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments.

ABSTRACT: Overexpression of transforming growth factor beta (TGF-beta) is frequently associated with metastasis and poor prognosis, and TGF-beta antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti-TGF-beta antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell-mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rae1gamma) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-beta expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-beta antibodies reverse this effect, and the absence of a major effect of TGF-beta antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications.

SUBMITTER: Nam JS

PROVIDER: S-EPMC2587151 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTGF? signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGF? signaling.MethodsTo test the importance of TGF? signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGF? response (FET), or tumorigenic with TGF? response (FET?) or tumorigenic with abrogated TGF? response via introduction of dominant negative TGF?RII (FET?/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging.ResultsAbrogation of TGF? signaling through introduction of a dominant negative TGF? receptor II (TGF?RII) in non-metastatic FET? human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGF? signaling in FET?-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGF? signaling is a metastasis suppressor, we rescued TGF? signaling in CBS metastatic colon cancer cells that had lost TGF? receptor expression due to epigenetic repression. Restoration of TGF? signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGF? signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma.ConclusionsThe observations presented here indicate a metastasis suppressor role for TGF? signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGF? signaling may be imprudent in some patient populations with residual TGF? tumor suppressor activity.

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An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments.

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