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Membrane versus soluble isoforms of TNF-? exert opposing effects on tumor growth and survival of tumor-associated myeloid cells.

ABSTRACT: TNF-?, produced by most malignant cells, orchestrates the interplay between malignant cells and myeloid cells, which have been linked to tumor growth and metastasis. Although TNF-? can exist as one of two isoforms, a 26-kDa membrane tethered form (mTNF-?) or a soluble 17-kDa cytokine (sTNF-?), the vast majority of published studies have only investigated the biologic effects of the soluble form. We show for the first time that membrane and soluble isoforms have diametrically opposing effects on both tumor growth and myeloid content. Mouse lung and melanoma tumor lines expressing mTNF-? generated small tumors devoid of monocytes versus respective control lines or lines expressing sTNF-?. The lack of myeloid cells was due to a direct effect of mTNF-? on myeloid survival via induction of cell necrosis by increasing reactive oxygen species. Human non-small cell lung carcinoma expressed varying levels of both soluble and membrane TNF-?, and gene expression patterns favoring mTNF-? were predictive of improved lung cancer survival. These data suggest that there are significant differences in the role of different TNF-? isoforms in tumor progression and the bioavailability of each isoform may distinctly regulate tumor progression. This insight is critical for effective intervention in cancer therapy with the available TNF-? inhibitors, which can block both TNF-? isoforms.

SUBMITTER: Ardestani S

PROVIDER: S-EPMC3702680 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Membrane versus soluble isoforms of TNF-α exert opposing effects on tumor growth and survival of tumor-associated myeloid cells.

Ardestani Shidrokh S Li Bin B Deskins Desirae L DL Wu Huiyun H Massion Pierre P PP Young Pampee P PP

Cancer research 20130523 13

TNF-α, produced by most malignant cells, orchestrates the interplay between malignant cells and myeloid cells, which have been linked to tumor growth and metastasis. Although TNF-α can exist as one of two isoforms, a 26-kDa membrane tethered form (mTNF-α) or a soluble 17-kDa cytokine (sTNF-α), the vast majority of published studies have only investigated the biologic effects of the soluble form. We show for the first time that membrane and soluble isoforms have diametrically opposing effects on ...[more]

PMID: 23704210

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Project description:BackgroundThe phosphatidylinositol 3-kinase-regulated protein kinase, Akt, plays an important role in the initiation and progression of human cancer. Mammalian cells express three Akt isoforms (Akt1-3), which are encoded by distinct genes. Despite sharing a high degree of amino acid identity, phenotypes observed in knockout mice suggest that Akt isoforms are not functionally redundant. The relative contributions of the different Akt isoforms to oncogenesis, and the effect of their deficiencies on tumor development, are not well understood.MethodsHere we demonstrate that Akt isoforms have non-overlapping and sometimes opposing functions in tumor initiation and progression using a viral oncogene-induced mouse model of lung cancer and Akt isoform-specific knockout mice.ResultsAkt1 ablation significantly delays initiation of lung tumor growth, whereas Akt2 deficiency dramatically accelerates tumorigenesis in this mouse model. Ablation of Akt3 had a small, not statistically significant, stimulatory effect on tumor induction and growth by the viral oncogene. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki67 immunostaining of lung tissue sections revealed that the delayed tumor induction in Akt1-/- mice was due to the inhibitory effects of Akt1 ablation on cell growth and survival. Conversely, the accelerated growth rate of lung tumors in Akt2-/- and Akt3-/- mice was due to increased cell proliferation and reduced tumor cell apoptosis. Investigation of Akt signaling in tumors from Akt knockout mice revealed that the lack of Akt1 interrupted the propagation of signaling in tumors to the critical downstream targets, GSK-3?/? and mTOR.ConclusionsThese results demonstrate that the degree of functional redundancy between Akt isoforms in the context of lung tumor initiation is minimal. Given that this mouse model exhibits considerable similarities to human lung cancer, these findings have important implications for the design and use of Akt inhibitors for the treatment of lung cancer.

Dataset Information

Membrane versus soluble isoforms of TNF-? exert opposing effects on tumor growth and survival of tumor-associated myeloid cells.

Publications

Membrane versus soluble isoforms of TNF-α exert opposing effects on tumor growth and survival of tumor-associated myeloid cells.

Similar Datasets

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