DIABESITY · Obesity, Type 2 diabetes and the increased risk of cancer and cancer-related Mortality
FP7 — People (Marie Curie Actions)
- Duration
- —
- EU contribution
- €250,106
- Participants
- 1
- Scheme
- FP7-PEOPLE-2011-IIF
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Results in brief
Obesity, Type 2 diabetes and the increased risk of cancer and cancer-related Mortality; the study of Molecular Mechanisms and potential therapeutic modalities.
The following specific aims were addressed in the research over the period of the grant. Specific Aims 1. To determine if the hyperinsulinemia in female MKR mice affects mammary tumor development and metastases to the lungs. The hyperinsulinemic MKR mice had orthotopic of mouse mammary cancer cells injected into the 4th mammary gland. Compared to wild type control mice the tumors grew more rapidly and there was increased lung metastases in the MKR mice. When cancer cells were injected into the tail vein there was similarly an increase in lung metastases, suggesting that the metastases was dependent on the hyperinsulinemia and not necessarily the size of the primary mammary gland tumors. We have developed cancer cell lines with knockdown (KD) of the insulin (IR) and IGF-1R using shRNA technology and implanted these cells into the mammary gland of the MKR mice. The IR-KD tumors grew slower (and had fewer metastases) compared to IGF-1R-KD and control tumors, supporting the conclusion that the IR is mediating the effect of hyperinsulinemia on mammary growth and metastases. Tumors were examined for gene expression analysis and pathway analysis and the tumors from hyperinsulinemia mice showed a specific pattern consistent with genes involved in growth, metastases and anti-apoptosis. We have also demonstrated that there is epithelial-mesenchymal transformation in the hyperinsulinemic tumors by demonstrating an increase in vimentin expression. 2. To determine if hypercholesterolemia in the ApoE-/- female mice affects mammary tumor development and metastases to the lungs. apoE-/- mice are dyslipidemia with high cholesterol and high triglyceride levels. Introducing mouse mammary tumor cells into the 4th mammary gland also led to increase primary tumor growth and more lung metastases compared with control mice. Cell culture experiments demonstrated that LDL cholesterol stimulated cell proliferation and was inhibited by lipid raft disruption. Cellular signaling involved increased p-AKT and inhibition of p-ERK; the latter due to an increase in a phosphatase. 3. To study the effect of insulin and cholesterol on mammary epithelial cell (MEC)- and MVT1 tumor-derived stem/progenitor cells. We have demonstrated that the MVT1 tumors used in the above experiments express a specific stem/progenitor cell marker, CD24. CD24 + cells are much more aggressive in cell culture and cause greater tumor growth in mice compared to CD24- cells. These stem cells explain the aggressiveness of the tumors in the hyperinsulinemic mice. In summary We have been successful in completing studies outlined in the specific aims and are continuing to pursue the studies in more depth
Data: CORDIS, © European Union
Project objective
;Epidemiological studies have clearly demonstrated that obesity and Type 2 diabetes are associated with an increased risk of developing common cancers including breast and colon cancer. They are also associated with increased cancer related mortality. While the mechanisms involved in this association are not yet defined, insulin resistance, hyperinsulinemia, hyperlipidemia, hyperglycemia and inflammatory cytokines are thought to be involved.Our studies, using separate mouse models of obesity or Type 2 diabetes, have replicated the increased association of these conditions and breast cancer. We have shown that endogenous hyperinsulinemia maybe an important contributing factor in the increased cancer risk. We propose to extend these studies in a number of directions. Firstly to confirm the findings using a mouse colon cancer cell lines. We will also study metastases, using a specific breast cancer cell line that spreads to the lungs and colon cancer that spreads to the liver. In these mouse experiments we will use specific blockers to the insulin and IGF-1 receptors to determine if the role of endogenous hyperinsulinemia is indeed a major factor in metastases and through which receptor it propagates a signaling cascade. Studies on the molecular mechanisms will be carried out on cells in culture and in the tissue samples from the tumors and metastases from lung and liver.We have also developed a model of hyperlipidemia and cancer and preliminary studies in our model suggest that, hyperlipidemia maybe another contributing factor in the connection between obesity/Type 2 diabetes and cancer and cancer metastases. This model, using breast and colon cancer, will be studied to identify the causative connection between this metabolic disorder and cancer.Overall the plan is to identify specific causality that will help design new therapeutic agents to deal with the growing problem of cancer in obese and diabetic patients.""
Original text from CORDIS.
Participants
- TECHNION - ISRAEL INSTITUTE OF TECHNOLOGY · HaifaCoordinatorIsrael
Links
Data: CORDIS, © European Union