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Lani · 04-15-2011, 08:23 AM

note: "potentially" benefiting from metformin

UK: New test identifies cancer patients to benefit from 10p-a-day diabetes drug
[University of Manchester (UK)]

Scientists have developed a new test which can identify which breast cancer patients could benefit from a 10p-a-day diabetes drug.

They used a new method based on the 'food' cancer cells eat to predict which patients would have poor prognosis. They suggest these patients could benefit from metformin, a cheap and safe diabetes drug that could be a revolutionary cancer treatment.

The findings come from the Breakthrough Breast Cancer Research Unit at The University of Manchester and Thomas Jefferson University in the USA and are published today (Friday) in the journal Cell Cycle.

Professor Michael Lisanti, from the Breakthrough Breast Cancer Research Unit at The University of Manchester, said: "We've shown that the saying, 'you are what you eat' holds true for cancer. The food cancer cells consume is crucial to how well a patient does and what treatment they need.

"If cancer cells are consuming high-energy food, this makes a tumour more aggressive and harder to treat. However, they could benefit from metformin, which cuts off this fuel supply. There is more work to do but this test could be an important new way of tailoring treatments to patients need, across a range of cancers."

Professor Lisanti's team first looked at cells in the laboratory and fed them high-energy food, known as lactates and ketones. They found which genes were expressed based on this fuel supply, and developed a gene signature based on this.

They then looked at 219 hormonal breast cancer patients and studied which cancer cells fed on ketones and lactates. This food comes both from cancer cells and healthy cells nearby. They found those patients with cancer cells that consumed high levels of ketones and lactates were more likely to have their disease return, for it to spread to other organs and to die. The test combines the gene signature with the ketone and lactate food supply. This could both show which patients are likely to have a poor prognosis - with those same patients potentially benefiting from metformin.

Professor Anthony Howell, Director of the Breakthrough Breast Cancer Research Unit in Manchester, said: "This is terrifically exciting. It is a step towards having each patient get the right treatment for them - what we call personalised medicine. We are looking at a new way to separate patients based on who should respond well to the treatments we have, and who might need something different.

"It is particularly encouraging that some of those treatments might already be in the doctor's drug cabinet, and cheap to prescribe. We have some way to go but we hope that drugs like metformin will be saving lives of breast cancer patients over the next few years."

ABSTRACT: Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling
[Cell Cycle]
Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)—producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. To test this model more directly, here we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a >4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the "Reverse Warburg Effect". Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels. In human breast cancer patients, a loss of stromal Cav-1 is associated with an increased risk of early tumor recurrence, metastasis, tamoxifen-resistance, and poor clinical outcome. Thus, loss of stromal Cav-1 may be an effective marker for predicting the "Reverse Warburg Effect" in the stroma of human breast cancer patients. As such, CL4 fibroblasts are a new attractive model for mimicking the "glycolytic phenotype" of cancer-associated fibroblasts. Nutrients derived from glycolytic cancer associated fibroblasts could provide an escape mechanism to confer drug-resistance during anti-angiogenic therapy, by effectively reducing the dependence of cancer cells on a vascular blood supply.

04-15-2011, 08:23 AM	#1
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	(? ready for prime time)--predicting which bc patients would benefit from metformin note: "potentially" benefiting from metformin UK: New test identifies cancer patients to benefit from 10p-a-day diabetes drug [University of Manchester (UK)] Scientists have developed a new test which can identify which breast cancer patients could benefit from a 10p-a-day diabetes drug. They used a new method based on the 'food' cancer cells eat to predict which patients would have poor prognosis. They suggest these patients could benefit from metformin, a cheap and safe diabetes drug that could be a revolutionary cancer treatment. The findings come from the Breakthrough Breast Cancer Research Unit at The University of Manchester and Thomas Jefferson University in the USA and are published today (Friday) in the journal Cell Cycle. Professor Michael Lisanti, from the Breakthrough Breast Cancer Research Unit at The University of Manchester, said: "We've shown that the saying, 'you are what you eat' holds true for cancer. The food cancer cells consume is crucial to how well a patient does and what treatment they need. "If cancer cells are consuming high-energy food, this makes a tumour more aggressive and harder to treat. However, they could benefit from metformin, which cuts off this fuel supply. There is more work to do but this test could be an important new way of tailoring treatments to patients need, across a range of cancers." Professor Lisanti's team first looked at cells in the laboratory and fed them high-energy food, known as lactates and ketones. They found which genes were expressed based on this fuel supply, and developed a gene signature based on this. They then looked at 219 hormonal breast cancer patients and studied which cancer cells fed on ketones and lactates. This food comes both from cancer cells and healthy cells nearby. They found those patients with cancer cells that consumed high levels of ketones and lactates were more likely to have their disease return, for it to spread to other organs and to die. The test combines the gene signature with the ketone and lactate food supply. This could both show which patients are likely to have a poor prognosis - with those same patients potentially benefiting from metformin. Professor Anthony Howell, Director of the Breakthrough Breast Cancer Research Unit in Manchester, said: "This is terrifically exciting. It is a step towards having each patient get the right treatment for them - what we call personalised medicine. We are looking at a new way to separate patients based on who should respond well to the treatments we have, and who might need something different. "It is particularly encouraging that some of those treatments might already be in the doctor's drug cabinet, and cheap to prescribe. We have some way to go but we hope that drugs like metformin will be saving lives of breast cancer patients over the next few years." ABSTRACT: Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling [Cell Cycle] Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)—producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. To test this model more directly, here we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a >4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the "Reverse Warburg Effect". Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels. In human breast cancer patients, a loss of stromal Cav-1 is associated with an increased risk of early tumor recurrence, metastasis, tamoxifen-resistance, and poor clinical outcome. Thus, loss of stromal Cav-1 may be an effective marker for predicting the "Reverse Warburg Effect" in the stroma of human breast cancer patients. As such, CL4 fibroblasts are a new attractive model for mimicking the "glycolytic phenotype" of cancer-associated fibroblasts. Nutrients derived from glycolytic cancer associated fibroblasts could provide an escape mechanism to confer drug-resistance during anti-angiogenic therapy, by effectively reducing the dependence of cancer cells on a vascular blood supply.