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Chng W.J.,National University of Singapore | Chng W.J.,Cancer Science Institute of Singapore | Dispenzieri A.,Mayo Medical School | Chim C.-S.,Queen Mary Hospital | And 11 more authors.
Leukemia | Year: 2014

Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable response to treatment and outcome. With the recent increase in treatment armamentarium and the projected further increase in approved therapeutic agents in the coming years, the issue of having some mechanism to dissect this heterogeneity and rationally apply treatment is coming to the fore. A number of robustly validated prognostic markers have been identified and the use of these markers in stratifying patients into different risk groups has been proposed. In this consensus statement, the International Myeloma Working Group propose well-defined and easily applicable risk categories based on current available information and suggests the use of this set of prognostic factors as gold standards in all clinical trials and form the basis of subsequent development of more complex prognostic system or better prognostic factors. At the same time, these risk categories serve as a framework to rationalize the use of therapies. © 2014 Macmillan Publishers Limited.

Kono K.,National University of Singapore | Kono K.,Cancer Science Institute of Singapore | Mimura K.,National University of Singapore
OncoImmunology | Year: 2013

Although it has been shown in murine models that chemoradiotherapy may induce immunogenic tumor cell death, which could trigger T-cell immunity upon the released of high-mobility group box 1 protein (HMGB1), whether this also occurs in clinical settings remains unclear. Here, we discuss tumor-antigen specific T-cell responses in esophageal cancer patients receiving chemoradiotherapy. Our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses and that the release of HMGB1 is related to clinical outcome. © 2013 Landes Bioscience.

Pattabiraman D.R.,Whitehead Institute For Biomedical Research | Bierie B.,Whitehead Institute For Biomedical Research | Kober K.I.,Whitehead Institute For Biomedical Research | Thiru P.,Whitehead Institute For Biomedical Research | And 8 more authors.
Science | Year: 2016

The epithelial-to-mesenchymal transition enables carcinoma cells to acquire malignancy-associated traits and the properties of tumor-initiating cells (TICs). TICs have emerged in recent years as important targets for cancer therapy, owing to their ability to drive clinical relapse and enable metastasis. Here, we propose a strategy to eliminate mesenchymal TICs by inducing their conversion to more epithelial counterparts that have lost tumor-initiating ability. We report that increases in intracellular levels of the second messenger, adenosine 3',5'-monophosphate, and the subsequent activation of protein kinase A (PKA) induce a mesenchymal-to-epithelial transition (MET) in mesenchymal human mammary epithelial cells. PKA activation triggers epigenetic reprogramming of TICs by the histone demethylase PHF2, which promotes their differentiation and loss of tumor-initiating ability. This study provides proof-of-principle for inducing an MET as differentiation therapy for TICs and uncovers a role for PKA in enforcing and maintaining the epithelial state.

Lee C.W.L.,Cancer Science Institute of Singapore | Lee C.W.L.,National University of Singapore | Lee C.W.L.,Institute of Molecular and Cell Biology | Ito K.,Nagasaki University | And 2 more authors.
Cancer Research | Year: 2010

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) superfamily, are multifunctional cytokines regulating a broad spectrum of biological functions. Recent studies show the presence of BMP receptor 1a mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer, suggesting that aberrations in BMP signaling play an important role in intestinal cancer pathogenesis. However, the exact molecular mechanisms remain poorly understood. The Runt domain transcription factor RUNX3 is an integral component of signaling pathways mediated by TGF-β and BMPs. RUNX3 is a gastric and colon tumor suppressor, functioning downstream of TGF-β. Recently, we showed the tumor-suppressive effects of RUNX3 by its ability to attenuate β-catenin/T-cell factors (TCFs) transactivation in intestinal tumorigenesis. Here, we explore the molecular basis of the tumor-suppressive function of the BMP pathway through RUNX3 in colorectal carcinogenesis. BMP exerted a growth-suppressive effect in HT-29, a human colorectal cancer cell line. c-Myc oncogene was found to be downregulated by BMP and/or RUNX3. We show that upregulation of RUNX3 by BMP reduces c-Myc expression. Evidence is presented suggesting that RUNX3 down-regulates c-Myc expression by two parallel pathways-directly at the transcriptional level and through attenuation of β-catenin/TCFs, downstream of BMPs in colorectal cancer cells. ©2010 AACR.

Akalay I.,French Institute of Health and Medical Research | Janji B.,CRP Sante | Hasmim M.,French Institute of Health and Medical Research | Noman M.Z.,French Institute of Health and Medical Research | And 15 more authors.
Cancer Research | Year: 2013

Epithelial-to-mesenchymal transition (EMT) mediates cancer cell invasion, metastasis, and drug resistance, but its impact on immune surveillance has not been explored. In this study, we investigated the functional consequences of this mode of epithelial cell plasticity on targeted cell lysis by cytotoxic T lymphocytes (CTL). Acquisition of the EMT phenotype in various derivatives of MCF-7 human breast cancer cells was associated with dramatic morphologic changes and actin cytoskeleton remodeling, with CD24-/CD44 +/ALDH+ stem cell populations present exhibiting a higher degree of EMT relative to parental cells. Strikingly, acquisition of this phenotype also associated with an inhibition of CTL-mediated tumor cell lysis. Resistant cells exhibited attenuation in the formation of an immunologic synapse with CTLs along with the induction of autophagy in the target cells. This response was critical for susceptibility to CTL-mediated lysis because siRNA-mediated silencing of beclin1 to inhibit autophagy in target cells restored their susceptibility to CTL-induced lysis. Our results argue that in addition to promoting invasion and metastasis EMT also profoundly alters the susceptibility of cancer cells to T-cell-mediated immune surveillance. Furthermore, they reveal EMT and autophagy as conceptual realms for immunotherapeutic strategies to block immune escape. Cancer Res; 73(8); 2418-27. © 2013 American Association for Cancer Research.

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