Clinical Research Institute at Rambam CRIR

Haifa, Israel

Clinical Research Institute at Rambam CRIR

Haifa, Israel
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Zelenko Z.,Mount Sinai School of Medicine | Gallagher E.J.,Mount Sinai School of Medicine | Tobin-Hess A.,Mount Sinai School of Medicine | Belardi V.,Mount Sinai School of Medicine | And 5 more authors.
Oncogene | Year: 2017

Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared with wild-type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells. Analysis of the primary tumors showed significant increase in vimentin protein expression in the MKR mice compared with WT. We hypothesized that vimentin was an important mediator in the effect of hyperinsulinemia on breast cancer metastasis. Lentiviral short hairpin RNA knockdown of vimentin led to a significant decrease in invasion of the MVT-1 cells and abrogated the increase in cell invasion in response to insulin. In the pre-diabetic MKR mouse, vimentin knockdown led to a decrease in pulmonary metastases. In vitro, we found that insulin increased pAKT, prevented caspase 3 activation, and increased vimentin. Inhibiting the phosphatidylinositol 3 kinase/AKT pathway, using NVP-BKM120, increased active caspase 3 and decreased vimentin levels. This study is the first to show that vimentin has an important role in tumor metastasis in vivo in the setting of pre-diabetes and endogenous hyperinsulinemia. Vimentin targeting may be an important therapeutic strategy to reduce metastases in patients with obesity, pre-diabetes or T2D. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


Rostoker R.,Clinical Research Institute at Rambam CRIR | Bitton-Worms K.,Clinical Research Institute at Rambam CRIR | Genkin I.,Clinical Research Institute at Rambam CRIR | Ben-Shmuel S.,Clinical Research Institute at Rambam CRIR | And 5 more authors.
Endocrine-Related Cancer | Year: 2015

Accumulating evidence from clinical trials indicates that specific targeting of the IGF1 receptor (IGF1R) is not efficient as an anti-breast cancer treatment. One possible reason is that the mitogenic signals from the insulin receptor (IR) can be processed independently or as compensation to inhibition of the IGF1R. In this study, we highlight the role of the IR in mediating breast tumor progression in both WT mice and a hyperinsulinemic MKR mouse model by induction of Ir (Insr) orIgf1r knockdown (KD) in the mammary carcinoma Mvt-1 cell line. By using the specific IR antagonist-S961, we demonstrated that Igf1r-KD induces elevated responses by the IR to IGF1. On the other hand, Ir-KD cells generated significantly smaller tumors in the mammary fat pads of both WT and MKR mice, as opposed to control cells, whereas the Igf1r-KD cells did not. The tumorigenic effects of insulin on the Mvt-1 cells were also demonstrated using microarray analysis, which indicates alteration of genes and signaling pathways involved in proliferation, the cell cycle, and apoptosis following insulin stimulation. In addition, the correlation between IR and the potential prognostic marker for aggressive breast cancer, CD24, was examined in the Ir-KD cells. Fluorescence-activated cell sorting (FACS) analysis revealed more than 60% reduction in CD24 expression in the Ir-KD cells when compared with the control cells. Our results also indicate that CD24-expressing cells can restore, at least in part, the tumorigenic capacity of Ir-KD cells. Taken together, our results highlight the mitogenic role of the IR in mammary tumor progression with a direct link to CD24 expression. © 2015 Society for Endocrinology.


Alikhani N.,Mount Sinai School of Medicine | Ferguson R.D.,Mount Sinai School of Medicine | Novosyadlyy R.,Mount Sinai School of Medicine | Gallagher E.J.,Mount Sinai School of Medicine | And 4 more authors.
Oncogene | Year: 2013

Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE -/-), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE -/- and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE -/- mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE -/- mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE -/- mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased AktS473 phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated AktS473 phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE -/- mice is a favorable setting for mammary tumor growth and metastasis. © 2013 Macmillan Publishers Limited All rights reserved.


Ferguson R.D.,Mount Sinai School of Medicine | Gallagher E.J.,Mount Sinai School of Medicine | Scheinman E.J.,Clinical Research Institute at Rambam CRIR | Damouni R.,Clinical Research Institute at Rambam CRIR | And 2 more authors.
Vitamins and Hormones | Year: 2013

The worldwide epidemic of obesity is associated with increasing rates of the metabolic syndrome and type 2 diabetes. Epidemiological studies have reported that these conditions are linked to increased rates of cancer incidence and mortality. Obesity, particularly abdominal obesity, is associated with insulin resistance and the development of dyslipidemia, hyperglycemia, and ultimately type 2 diabetes. Although many metabolic abnormalities occur with obesity and type 2 diabetes, insulin resistance and hyperinsulinemia appear to be central to these conditions and may contribute to dyslipidemia and altered levels of circulating estrogens and androgens. In this review, we will discuss the epidemiological and molecular links between obesity, type 2 diabetes, and cancer, and how hyperinsulinemia and dyslipidemia may contribute to cancer development. We will discuss how these metabolic abnormalities may interact with estrogen signaling in breast cancer growth. Finally, we will discuss the effects of type 2 diabetes medications on cancer risk. © 2013 Elsevier Inc.


Rostoker R.,Clinical Research Institute at Rambam CRIR | Ben-Shmuel S.,Clinical Research Institute at Rambam CRIR | Rashed R.,Clinical Research Institute at Rambam CRIR | Rashed R.,Technion - Israel Institute of Technology | And 2 more authors.
Breast Cancer Research | Year: 2016

Background: The pro-tumorigenic effects of the insulin-like growth factor receptor (IGF1R) are well described. IGF1R promotes cancer cell survival and proliferation and prevents apoptosis, and, additionally it was shown that IGF1R levels are significantly elevated in most common human malignancies including breast cancer. However, results from phase 3 clinical trials in unselected patients demonstrated lack of efficacy for anti-IGF1R therapy. These findings suggest that predictive biomarkers are greatly warranted in order to identify patients that will benefit from anti-IGF1R therapeutic strategies. Methods: Using the delivery of shRNA vectors into the Mvt1 cell line, we tested the role of the IGF1R in the development of mammary tumors. Based on CD24 cell surface expression, control and IGF1R-knockdown (IGF1R-KD) cells were FACS sorted into CD24- and CD24+ subsets and further characterized in vitro. The tumorigenic capacity of each was determined following orthotopic inoculation into the mammary fat pad of female mice. Tumor cells were FACS characterized upon sacrifice to determine IGF1R effect on the plasticity of this cell's phenotype. Metastatic capacity of the cells was assessed using the tail vein assay. Results: In this study we demonstrate that downregulation of the IGF1R specifically in cancer cells expressing CD24 on the cell surface membrane affect both their morphology (from mesenchymal-like into epithelial-like morphology) and phenotype in vitro. Moreover, we demonstrate that IGF1R-KD abolished both CD24+ cells capacity to form mammary tumors and lung metastatic lesions. We found in both cells and tumors a marked upregulation in CTFG and a significant reduction of SLP1 expression in the CD24+/IGF1R-KD; tumor-suppressor and tumor-promoting genes respectively. Moreover, we demonstrate here that the IGF1R is essential for the maintenance of stem/progenitor-like cancer cells and we further demonstrate that IGF1R-KD induces in vivo differentiation of the CD24+ cells toward the CD24- phenotype. This further supports the antitumorigenic effects of IGF1R-KD, as we recently published that these differentiated cells demonstrate significantly lower tumorigenic capacity compared with their CD24+ counterparts. Conclusions: Taken together these findings suggest that CD24 cell surface expression may serve as a valuable biomarker in order to identify mammary tumors that will positively respond to targeted IGF1R therapies. © 2016 Rostoker et al.


Scheinman E.J.,Clinical Research Institute at Rambam CRIR | Rostoker R.,Clinical Research Institute at Rambam CRIR | LeRoith D.,Clinical Research Institute at Rambam CRIR
Molecular and Cellular Endocrinology | Year: 2013

Hyperlipidemia and hypercholesterolemia have been found to be important factors in cancer development and metastasis. However, the metabolic mechanism and downstream cellular processes following cholesterol stimulation are still unknown. Here we tested the effect of cholesterol on MC-38 colon cancer cells. Using Illumina gene array technology we found a number of genes that were differentially expressed following short term (20-40. min) and longer term (between 2 and 5. h) cholesterol stimulation. Three genes were consistently increased at these time points; c-Jun, Jun-B and the chemokine CXCL-1. We have previously shown that cholesterol stimulation leads to PI3K/Akt phosphorylation, and now demonstrated that cholesterol inhibits ERK1/2 phosphorylation; both effects reversed when cholesterol is depleted from lipid rafts using methyl-β-cyclodextrin (MBCD). In addition, vanadate, an inhibitor of phosphatases, reversed the cholesterol inhibition of ERK1/2 phosphorylation. Specific inhibition of p-Akt by wortmannin did not affect cholesterol's stimulation of the expression of c-Jun and Jun-B, however the vanadate effect of increasing p-ERK1/2, inhibited c-Jun expression, specifically, and the MBCD effect of increasing p-ERK and inhibiting p-Akt reduced c-Jun expression. In contrast MBCD and vanadate both enhanced Jun-B gene expression in the presence of cholesterol and elevation of ERK phosphorylation. Thus there is apparently, a differential signaling pathway whereby cholesterol enhances gene expression of the Jun family members. © 2013 Elsevier Ireland Ltd.


Bitton-Worms K.,Clinical Research Institute at Rambam CRIR | Rostoker R.,Clinical Research Institute at Rambam CRIR | Braun S.,Clinical Research Institute at Rambam CRIR | Shen-Orr Z.,Clinical Research Institute at Rambam CRIR | Leroith D.,Clinical Research Institute at Rambam CRIR
Hormone and Metabolic Research | Year: 2013

Obesity is associated with hyperleptinemia and this has led to the suggestion that leptin maybe a factor in cancer progression. To study the effect of leptin on cancer progression we used a mouse model of diabetes that was shown to enhance tumor progression and thereby determine if leptin affects cancer progression despite improvements in metabolic status. Mammary tumors were allowed to develop in male and female mice following orthotopic injection of cells expressing oncogenes. After 2 weeks leptin was administered to the mice using Alzet pumps. In these mice leptin failed to stimulate tumor progression; indeed, in those studies where glucose tolerance improved tumor growth was actually inhibited. Thus, the possibility exists that the effect of leptin on tumor progression maybe opposed by improvements in metabolism. © 2013 Georg Thieme Verlag KG Stuttgart · New York.


PubMed | Mount Sinai School of Medicine, Girihlet Inc. and Clinical Research Institute at Rambam CRIR
Type: | Journal: Genomics data | Year: 2015

CD24 is an anchored cell surface marker that is highly expressed in cancer cells (Lee et al., 2009) and its expression is associated with poorer outcome of cancer patients (Kristiansen et al., 2003). Phenotype comparison between two subpopulations derived from the Mvt1 cell line, CD24(-) cells (with no CD24 cell surface expression) and the CD24(+) cells, identified high tumorigenic capacity for the CD24(+) cells. In order to reveal the transcripts that support the CD24(+) aggressive and invasive phenotype we compared the gene profiles of these two subpopulations. mRNA profiles of CD24(-) and CD24(+) cells were generated by deep sequencing, in triplicate, using an Illumina HiSeq 2500. Here we provide a detailed description of the mRNA-seq analysis from our recent study (Rostoker et al., 2015). The mRNA-seq data have been deposited in the NCBI GEO database (accession number GSE68746).


PubMed | Clinical Research Institute at Rambam CRIR
Type: Journal Article | Journal: Breast cancer research : BCR | Year: 2016

The pro-tumorigenic effects of the insulin-like growth factor receptor (IGF1R) are well described. IGF1R promotes cancer cell survival and proliferation and prevents apoptosis, and, additionally it was shown that IGF1R levels are significantly elevated in most common human malignancies including breast cancer. However, results from phase 3 clinical trials in unselected patients demonstrated lack of efficacy for anti-IGF1R therapy. These findings suggest that predictive biomarkers are greatly warranted in order to identify patients that will benefit from anti-IGF1R therapeutic strategies.Using the delivery of shRNA vectors into the Mvt1 cell line, we tested the role of the IGF1R in the development of mammary tumors. Based on CD24 cell surface expression, control and IGF1R-knockdown (IGF1R-KD) cells were FACS sorted into CD24(-) and CD24(+) subsets and further characterized in vitro. The tumorigenic capacity of each was determined following orthotopic inoculation into the mammary fat pad of female mice. Tumor cells were FACS characterized upon sacrifice to determine IGF1R effect on the plasticity of this cells phenotype. Metastatic capacity of the cells was assessed using the tail vein assay.In this study we demonstrate that downregulation of the IGF1R specifically in cancer cells expressing CD24 on the cell surface membrane affect both their morphology (from mesenchymal-like into epithelial-like morphology) and phenotype in vitro. Moreover, we demonstrate that IGF1R-KD abolished both CD24(+) cells capacity to form mammary tumors and lung metastatic lesions. We found in both cells and tumors a marked upregulation in CTFG and a significant reduction of SLP1 expression in the CD24(+)/IGF1R-KD; tumor-suppressor and tumor-promoting genes respectively. Moreover, we demonstrate here that the IGF1R is essential for the maintenance of stem/progenitor-like cancer cells and we further demonstrate that IGF1R-KD induces in vivo differentiation of the CD24(+) cells toward the CD24(-) phenotype. This further supports the antitumorigenic effects of IGF1R-KD, as we recently published that these differentiated cells demonstrate significantly lower tumorigenic capacity compared with their CD24(+) counterparts.Taken together these findings suggest that CD24 cell surface expression may serve as a valuable biomarker in order to identify mammary tumors that will positively respond to targeted IGF1R therapies.


PubMed | Clinical Research Institute at Rambam CRIR
Type: | Journal: Handbook of experimental pharmacology | Year: 2016

Obesity is associated with multiple metabolic disorders that drive cardiovascular disease, T2D and cancer. The doubling in the number of obese adults over the past 3 decades led to the recognition of obesity as a disease. With over 42 million children obese or overweight, this epidemic is rapidly growing worldwide. Obesity and T2D are both associated together and independently with an increased risk for cancer and a worse prognosis. Accumulating evidence from epidemiological studies revealed potential factors that may explain the association between obesity-linked metabolic disorders and cancer risk. Studies based on the insulin resistance MKR mice, highlighted the roe of the insulin receptor and its downstream signaling proteins in mediating hyperinsulinemias mitogenic effects. Hypercholesterolemia was also shown to promote the formation of larger tumors and enhancement in metastasis. Furthermore, the conversion of cholesterol into 27-Hydroxycholesterol was found to link high fat diet-induced hypercholesterolemia with cancer pathophysiology. Alteration in circulating adipokines and cytokines are commonly found in obesity and T2D. Adipokines are involved in tumor growth through multiple mechanisms including mTOR, VEGF and cyclins. In addition, adipose tissues are known to recruit and alter macrophage phenotype; these macrophages can promote cancer progression by secreting inflammatory cytokines such as TNF- and IL-6. Better characterization on the above factors and their downstream effects is required in order to translate the current knowledge into the clinic, but more importantly is to understand which are the key factors that drive cancer in each patient. Until we reach this point, policies and activities toward healthy diets and physical activities remain the best medicine.

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