Summary Gamma-secretase inhibitors (GSIs) block the activation of oncogenic NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of Klf4, a negative regulator of cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of Ccnd2 and protected mice from developing intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.

Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriched populations in mouse primary mammary tumor and breast cancer cell lines. Knockdown of KLF4 in breast cancer cells (MCF-7 and MDA-MB-231) decreased the proportion of stem/progenitor cells as demonstrated by expression of stem cell surface markers such as aldehyde dehydrogenase 1 (ALDH1), side-population (SP), and by in vitro mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation in vitro and inhibited tumorigenesis in immunocompromised NOD/SCID mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 plays a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell-like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer.

Histidine decarboxylase (HDC), the unique enzyme responsible for histamine generation, is highly expressed in myeloid cells but its function is poorly understood. Here, we show that Hdc knockout mice exhibit a markedly increased rate of colon and skin carcinogenesis. Using Hdc-EGFP BAC transgenic mice, we demonstrate that Hdc is expressed primarily in CD11b+Ly6G+ immature myeloid cells (IMCs) that are recruited early on in chemical carcinogenesis. Transplant of Hdc-deficient bone marrow to wildtype recipients results in increased CD11b+Ly6G+ cell mobilization and reproduces the cancer susceptibility phenotype. In addition, IMCs from Hdc knockout mice promote the growth of cancer xenografts and colon cancer cells downregulate Hdc expression through promoter hypermethylation and inhibits myeloid cell maturation. Exogenous histamine induces the differentiation of IMCs and suppresses their ability to support the growth of xenografts. These data indicate key roles for Hdc and histamine in myeloid cell differentiation, and CD11b+Ly6G+ IMCs in early cancer development.

Immune cells in tumor microenvironment play a prominent role in tumor progression and metastasis. represents an important player in innate and adaptive immunity by regulating differentiation, maturation and activation of macrophages, dendritic cells, B cells and T cells. However, the role of miR-155 expression in immune cells in solid tumor development is less elucidated. Our current study showed that both B16-F10 melanoma and Lewis lung carcinoma tumors grew much faster in bic/miR-155 knockout (miR-155 2/2 ) mice along with an increase of myeloid-derived suppressor cells (MDSCs) accumulation in tumors, compared to that in wild-type mice. Bone marrow transplantation study showed that bone marrow miR-155 deficiency could replicate the above tumor-promoting phenotype. In vitro study demonstrated that tumor-infiltrating miR-155 2/2 MDSCs showed greater migration ability and expressed higher level of multiple chemokines. Furthermore, we found that the level of HIF1a, a direct target of miR-155, was increased in miR-155 deficient MDSCs, and that the increased HIF-1a upregulated CXCL1, CXCL3 and CXCL8 expression in MDSCs, contributing to the enhanced recruitment of miR-155 2/2 MDSCs to the tumors. Moreover, miR-155 2/2 MDSCs showed enhanced immunosuppressive and pro-angiogenic capacities. Taken together, our study, for the first time, demonstrated that miR-155 deficiency promoted solid tumor growth through increasing the recruitment of MDSCs to tumor microenvironment and enhancing the tumor-promoting functions of the recruited MDSCs. Thus, upregulating miR-155 expression in MDSCs may be developed as a therapeutic approach to halt tumor development.Tumor progression is supported by chronic inflammatory microenvironment which is characterized by continuous secretion of inflammatory factors and infiltration of a variety of leukocytes. 1-4 Among them, myeloid-derived suppressor cells (MDSCs), defined as Gr-1 1 CD11b 1 cells in mice, represent one of the most important players. 5 MDSCs have been demonstrated to promote tumor progression by disturbing host immune responses, promoting tumor cell proliferation, migration and invasion, and enhancing angiogenesis. [6][7][8][9][10] In addition, infiltration of MDSCs in primary tumor sites and metastatic organs is a major obstacle to effective antitumor therapies. 11,12 For example, recruitment of MDSCs in certain tumors is responsible for the refractoriness to anti-VEGF treatment. 11 Thus, better understanding the molecular mechanisms underlying MDSC expansion, recruitment and activation is critical for developing more effective cancer therapeutic strategies.It has been show that microRNA-155 (miR-155) is upregulated in several solid tumors and B-cell lymphomas, and overexpression of miR-155 in tumor cells correlates with tumor aggressiveness in animal models. [13][14][15] Clinical studies have also suggested that high expression level of miR-155 in Tumor Immunology