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Copper and angiogenesis—a new piece to the puzzle
Newsdesk Copper and angiogenesis—a new piece to the puzzle erested in this approach for the treatment of cancer. He had developed the anticopper agent tetrathiomolybdane (TM) for the treatment of Wilson’s disease, a genetic disorder that results in brain and liver damage due to the abnormal accumulation of copper. “Studying the literature, it occurred to me that TM may [have] an antiangiogenic effect”, recalls Brewer. He approached his colleague at the University of Michigan, Sofia Merajver, a breast-cancer specialist who was looking for a global approach to inhibit angiogenesis at the time. Together, they showed that TM can safely arrest tumour growth in mice and humans with metastatic breast
Self-examination doesn’t work A major study by a group from the Fred Hutchinson Cancer Research Center, WA, USA, has shown that educating women to self-examine their breasts does not reduce mortality from breast cancer. David Thomas and colleagues randomly assigned 266 064 factory workers in Shanghai to either a breast self-examination instruction group or to a control group. Women in the selfexamination group were taught how to correctly examine their breasts and had reinforcement sessions 1 and 3 years later. They also received regular reminders to examine their breasts monthly and had medical supervision every 6 months for 5 years. The control group received no information on breast-cancer screening. After 10–11 years, there was no difference in breast-cancer mortality between the self-examination and control groups. Thomas says the results are disappointing: “It would have been really good to have found that breast self-examination is beneficial. For public-health officials in countries where mammographic screening is unavailable, my message is that they should not spend limited resources on programmes to teach women in the general population how to examine their breasts”, he explains.
“Such programmes would be very unlikely to reduce mortality from breast cancer. For women in countries where mammography is available, the message is that self-examination is not a substitute for regular mammography screening.” Linda Kinsinger (University of North Carolina at Chapel Hill, USA) believes that the study “provides what seems to be a definitive finding about the lack of effectiveness of teaching women self-examination in order to reduce breast-cancer mortality. Not only was there no benefit, the study also clearly demonstrated some harm, in terms of more biopsies for benign lumps.” She also feels that although women should be aware of breast cancer, few will have the necessary skill to carry out an effective examination. Looking to the future, Thomas says that the only method which may reduce mortality from breast cancer is mammography screening and it is uncertain whether self-examination has any additional benefits. Kinsinger adds that improved methods of identifying women who are at high risk for breast cancer and safer drugs for chemoprevention are more likely to reduce mortality. Cathel Kerr
3) Endothelial cells receive less angiogenic stimulation NF⌲B Normal epithelial cell
FGF2
1) Normal and cancer cells synthesize lower levels of pro-angiogenic factors FGF2
NF⌲B
Cancer cell 2) Copper deficiency interferes with the release of FGF2
Lymphocyte
Courtesy of Restless Imagination Productions
Scientists have come close to solving the mystery of why copper is required for angiogenesis, which, according to Steven Brem (Moffitt Cancer Center, FL, USA), is a “beautiful and very important piece of work”. Although it has been known since the 1980s that copper is a key factor in the regulation of angiogenic pathways, the precise mechanism remained unclear. However, Brem and others provided ample evidence that angiogenesis can be inhibited and tumour growth can be arrested by treatment with anticopper drugs, such as penicillamine (Am J Pathol 1990; 137: 1121–42). George Brewer at the University of Michigan (MI, USA) also became int-
Effects of copper deficiency.
cancer (Clin Cancer Res 2000; 6: 1–10). But Brewer and Merajver were also keen to explain why the anticopper strategy works. “We finally have the big picture”, says Merajver. In a recent study (Cancer Res 2002; 62: 4854–59), they found that in vitro treatment with TM inhibits transcription mediated by NFB in inflammatory breast cancer cells and thereby prevents cancer cells from releasing NFB-dependent mediators of angiogenesis, such as VEGF. The paper also confirms that breast-cancer development can be suppressed by copper deficiency. Transgenic Her2/neu mice did not develop breast cancer while being treated with TM for more than 7 months. When therapy was discontinued, a third of the mice developed measurable tumours within 2 weeks. Brem believes the implications of these findings are very exciting: “The role of copper deficiency in the clinic could be as a chemopreventive strategy in patients at high risk of cancer or recurrence after primary therapy. Because the NFB gene is linked to radioresistance and chemoresistance, copper deficiency could also potentiate chemotherapy and radiation therapy.” Brewer and Merajver are looking at various treatment options. “We have 11 phase II trials testing TM,” says Merajver. The drug is being given to patients with prostate cancer, head and neck cancer, multiple myeloma, and mesothelioma, both on its own and in combination with chemotherapy. Martina Habeck
650
THE LANCET Oncology Vol 3 November 2002
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Self-examination doesn’t work A major study by a group from the Fred Hutchinson Cancer Research Center, WA, USA, has shown that educating women to self-examine their breasts does not reduce mortality from breast cancer. David Thomas and colleagues randomly assigned 266 064 factory workers in Shanghai to either a breast self-examination instruction group or to a control group. Women in the selfexamination group were taught how to correctly examine their breasts and had reinforcement sessions 1 and 3 years later. They also received regular reminders to examine their breasts monthly and had medical supervision every 6 months for 5 years. The control group received no information on breast-cancer screening. After 10–11 years, there was no difference in breast-cancer mortality between the self-examination and control groups. Thomas says the results are disappointing: “It would have been really good to have found that breast self-examination is beneficial. For public-health officials in countries where mammographic screening is unavailable, my message is that they should not spend limited resources on programmes to teach women in the general population how to examine their breasts”, he explains.
“Such programmes would be very unlikely to reduce mortality from breast cancer. For women in countries where mammography is available, the message is that self-examination is not a substitute for regular mammography screening.” Linda Kinsinger (University of North Carolina at Chapel Hill, USA) believes that the study “provides what seems to be a definitive finding about the lack of effectiveness of teaching women self-examination in order to reduce breast-cancer mortality. Not only was there no benefit, the study also clearly demonstrated some harm, in terms of more biopsies for benign lumps.” She also feels that although women should be aware of breast cancer, few will have the necessary skill to carry out an effective examination. Looking to the future, Thomas says that the only method which may reduce mortality from breast cancer is mammography screening and it is uncertain whether self-examination has any additional benefits. Kinsinger adds that improved methods of identifying women who are at high risk for breast cancer and safer drugs for chemoprevention are more likely to reduce mortality. Cathel Kerr
3) Endothelial cells receive less angiogenic stimulation NF⌲B Normal epithelial cell
FGF2
1) Normal and cancer cells synthesize lower levels of pro-angiogenic factors FGF2
NF⌲B
Cancer cell 2) Copper deficiency interferes with the release of FGF2
Lymphocyte
Courtesy of Restless Imagination Productions
Scientists have come close to solving the mystery of why copper is required for angiogenesis, which, according to Steven Brem (Moffitt Cancer Center, FL, USA), is a “beautiful and very important piece of work”. Although it has been known since the 1980s that copper is a key factor in the regulation of angiogenic pathways, the precise mechanism remained unclear. However, Brem and others provided ample evidence that angiogenesis can be inhibited and tumour growth can be arrested by treatment with anticopper drugs, such as penicillamine (Am J Pathol 1990; 137: 1121–42). George Brewer at the University of Michigan (MI, USA) also became int-
Effects of copper deficiency.
cancer (Clin Cancer Res 2000; 6: 1–10). But Brewer and Merajver were also keen to explain why the anticopper strategy works. “We finally have the big picture”, says Merajver. In a recent study (Cancer Res 2002; 62: 4854–59), they found that in vitro treatment with TM inhibits transcription mediated by NFB in inflammatory breast cancer cells and thereby prevents cancer cells from releasing NFB-dependent mediators of angiogenesis, such as VEGF. The paper also confirms that breast-cancer development can be suppressed by copper deficiency. Transgenic Her2/neu mice did not develop breast cancer while being treated with TM for more than 7 months. When therapy was discontinued, a third of the mice developed measurable tumours within 2 weeks. Brem believes the implications of these findings are very exciting: “The role of copper deficiency in the clinic could be as a chemopreventive strategy in patients at high risk of cancer or recurrence after primary therapy. Because the NFB gene is linked to radioresistance and chemoresistance, copper deficiency could also potentiate chemotherapy and radiation therapy.” Brewer and Merajver are looking at various treatment options. “We have 11 phase II trials testing TM,” says Merajver. The drug is being given to patients with prostate cancer, head and neck cancer, multiple myeloma, and mesothelioma, both on its own and in combination with chemotherapy. Martina Habeck
650
THE LANCET Oncology Vol 3 November 2002
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.