Transforming growth factor β (TGFβ) is an effector of immune suppression and contributes to a permissive tumor microenvironment that compromises effective immunotherapy. We identified a correlation between TGFB1 and genes expressed by myeloid cells, but not granulocytes, in TCGA lung adenocarcinoma data, in which high TGFB1 expression was associated with poor survival. To determine whether TGFβ affected cell fate decisions and lineage commitment, we studied primary cultures of CD14+ monocytes isolated from peripheral blood of healthy donors. We discovered that TGFβ was a survival factor for CD14+ monocytes, which rapidly executed an apoptotic program in its absence. Continued exposure to TGFβ in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 6 (IL6) amplified HLA-DRlowCD14+CD11b+CD33+ myeloid derived suppressor cells (MDSCs) at the expense of macrophage and dendritic cell (DC) differentiation. MDSCs generated in the presence of TGFβ were more effective in suppressing T-cell proliferation and promoted the T regulatory cell phenotype. In contrast, inhibition of TGFβ signaling using a small molecule inhibitor of receptor kinase activity in CD14+ monocytes treated with GM-CSF and IL6 decreased MDSC differentiation and increased differentiation to pro-inflammatory macrophages and antigen-presenting DCs. The effect of autocrine and paracrine TGFβ on myeloid cell survival and lineage commitment suggests that pharmacological inhibition of TGFβ-dependent signaling in cancer would favor antitumor immunity.

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Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

Transforming growth factor β (TGFβ) plays critical roles in regulating a plethora of physiological processes in normal organs, including morphogenesis, embryonic development, stem cell differentiation, immune regulation, and wound healing. Though considered a tumor suppressor, TGFβ is a critical mediator of tumor microenvironment, in which it likewise mediates tumor and stromal cell phenotype, recruitment, inflammation, immune function and angiogenesis. The fact that activation of TGFβ is an early and persistent event in irradiated tissues and that TGFβ signaling controls effective DNA damage response provides a new means to understand both tissue and tumor responses to radiation. Here we discuss pre-clinical studies unraveling TGFβ effects in radiation responses and review TGFβ biology in lung cancer as an example of the opportunities for TGFβ pathway inhibition as a pharmaceutical approach to augment radiation therapy.

To identify the clinical features and independent predictors of survival in patients with bone metastases from prostate cancer (PCa). We retrospectively analysed 115 PCa patients with bone metastases between 1997 and 2009. The overall survival rate after bone metastases was calculated using the Kaplan-Meier method. The prognostic factors were identified by univariate analysis using a log-rank test and by multivariate analysis using Cox proportional hazards regression models. The follow-up rate was 100%, the follow-up cases during 1, 3 and 5 years were 103, 79 and 55, respectively. The 1-, 3-and 5-year survival rates were 89.1%, 60.9% and 49.8%, respectively, with a median survival time of 48.5 months for patients with bone metastases from PCa. In univariate analysis, age, Gleason score, clinical stage, the number of bone lesions, alkaline phosphatase (ALP) level, invasion of neighbouring organs and non-regional lymph node metastases were correlated with prognosis. By multivariate analysis using Cox regression, ALP level, Gleason score and non-regional lymph node metastases were independent prognostic factors. These prognostic factors will help us to determine the appropriate dose and fraction of radiotherapy for these patients. INTRODUCTIONProstate cancer (PCa), the most common carcinoma in the industrialised world, has had increasing incidence in China. It is the only solid tumour diagnosed with its first recurrence as bone metastases instead of visceral metastases. 1 The bones are among the most frequent distant metastatic sites for PCa, occurring in 85%-100% patients. 2 Some studies 3-5 have been undertaken to identify prognostic factors for PCa, but less research has been undertaken on bone metastases regularity, especially on the Chinese mainland.In this retrospective study, 115 cases of PCa with bone metastases were collected, and the clinical features and main prognostic factors, including age, Gleason score, stage, endocrine therapy, castration, radiotherapy, number of bone lesions, prostate-specific antigen (PSA) and alkaline phosphatase (ALP) levels, neighbouring organ metastases, regional and remote lymph node metastases, surrounding parenchyma invaded and other visceral metastases were analysed to determine treatment strategies and to predict the reactions of the patients to treatment.