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Canadian researchers uncover vital new clues in cancer
Newsdesk
Until now, scientists have been baffled by the ability of tumour cells to evade natural killer cells, which form an integral part of the immune surveillance system. New research provides an important breakthrough by identifying a receptor that not only mediates cytotoxic cell death but also has a role in transplant rejection. Previous findings had indicated that cytotoxic cell death in response to a virus, cancer, or immune rejection was triggered by granzyme B, an enzyme that activates cell-death proteases and triggers apoptosis. Entry of granzyme B into the cell was thought to be preceded by puncturing of the cell with another enzyme, perforin. But Chris Bleackley (University of Alberta, Edmonton, Canada) and colleagues have shown that cell death can be achieved in a perforin-independent way and raise the possibility of a specific receptor for granzyme B. They have now identified this cell surface receptor (mannose 6-phosphate/insulin-like growth factor II receptor) and, according to Bleackley, have solved “one of the biggest mysteries in cancer”.
Bleackley and colleagues found that mammalian cell lines deficient in the receptor did not undergo apoptosis when treated with granzyme B (Cell 2000; 103: 491–500). In addition, 7 days after they introduced allogenic grafts into laboratory mice, donor cells expressing the receptors were completely rejected, whereas cells lacking them survived, indicating that the receptors also have a role in transplant rejection. “An extracellular receptor-ligand interaction is an appealing target for drug development”, says Bleackley, adding that “inhibition of this interaction would also lead to immunosuppression in transplants”. Recent studies have shown the receptor to be absent from a wide variety of cancers, including those of breast, liver, ovary, and skin. Bleackley suggests that tumours with low expression of the receptor would not take up granzyme B, and they would therefore be refractory to killer T cells. He predicts, “If there is some way of re-establishing expression of the receptor in the tumours, the sensitivity to killers would return”.
Courtesy of B Motyka
Canadian researchers uncover vital new clues in cancer
Laser scanning confocal microscope image of a murine fibroblast line (L cells) after incubation with fluorescently tagged granzyme B.
These findings could completely alter the way doctors treat cancer and lead to new treatments for autoimmune diseases such as diabetes and rheumatoid arthritis, as well as preventing rejection of transplanted organs. Pharmaceutical companies are expected to begin soon to search for compounds that either block or stimulate the mannose 6phosphate/insulin-like growth factor II receptor. Jamal Nasir
Breast reconstruction cannot exorcise phantom pain Phantom breast syndrome, unlike phantoms reported after loss of a limb, tends not to fade with time but may remain disturbing for years. The symptoms range from itching to intermittent shooting pains in the missing tissue. Under-reporting of the syndrome is suspected, though small surveys show that the majority of mastectomy patients experience phantom sensation and up to 40% suffer pain. Now, a larger study carried out by Raja and co-workers (John Hopkins Medical Institutions, Baltimore, USA), has shown that pain persists even after reconstructive surgery has restored the appearance of normality. At a recent meeting of the American Society of Anesthesiologists, Raja and colleagues presented the analysis of questionnaires completed by 279 of 504 women who had undergone 200
mastectomy over a 3-year period. Almost 50% of the women had reconstructive surgery, two thirds of these by muscle transfer from the abdominal wall (TRAM-flaps), with the remainder opting for silicone or saline implants. Throbbing, unpleasant itching, pins and needles, and pressure were reported by 109 women, and phantom pain was reported by 87, with no significant differences in pain occurrence, intensity, or duration in relation to reconstructive surgery. In all, 31% of the mastectomy-only group and 35% of the reconstructive-surgery group reported pain. The true problem lies in the brain. The existence of pain before mastectomy is the strongest risk factor, which suggests that pain pathways have been reinforced. After mastectomy, cortical areas no longer sense the amputated breast, and take
stimuli from the surrounding shoulder. This information conflicts with vision, sense of balance, and muscle proprioception, and in a cortex already primed by previous pain, the result can be severe. Current treatments include creams based on capsaicin to provide temporary relief. In future, we may be able to attack the problem at its root. “I am optimistic,” says John Harris (University of Otago Medical School, Dunedin, New Zealand), who uses the cortical basis of pathological pain to develop treatments, “that therapeutic regimens, perhaps quite simple ones involving touch, manipulation, and visual observation of the reconstructed breast and surrounding tissues, might be effective”. For now, surgery results may fool the eye but the brain is not so easily persuaded. Janet Stephenson
THE LANCET Oncology Vol 1 December 2000
For personal use only. Not to be reproduced without permission of The Lancet.
Until now, scientists have been baffled by the ability of tumour cells to evade natural killer cells, which form an integral part of the immune surveillance system. New research provides an important breakthrough by identifying a receptor that not only mediates cytotoxic cell death but also has a role in transplant rejection. Previous findings had indicated that cytotoxic cell death in response to a virus, cancer, or immune rejection was triggered by granzyme B, an enzyme that activates cell-death proteases and triggers apoptosis. Entry of granzyme B into the cell was thought to be preceded by puncturing of the cell with another enzyme, perforin. But Chris Bleackley (University of Alberta, Edmonton, Canada) and colleagues have shown that cell death can be achieved in a perforin-independent way and raise the possibility of a specific receptor for granzyme B. They have now identified this cell surface receptor (mannose 6-phosphate/insulin-like growth factor II receptor) and, according to Bleackley, have solved “one of the biggest mysteries in cancer”.
Bleackley and colleagues found that mammalian cell lines deficient in the receptor did not undergo apoptosis when treated with granzyme B (Cell 2000; 103: 491–500). In addition, 7 days after they introduced allogenic grafts into laboratory mice, donor cells expressing the receptors were completely rejected, whereas cells lacking them survived, indicating that the receptors also have a role in transplant rejection. “An extracellular receptor-ligand interaction is an appealing target for drug development”, says Bleackley, adding that “inhibition of this interaction would also lead to immunosuppression in transplants”. Recent studies have shown the receptor to be absent from a wide variety of cancers, including those of breast, liver, ovary, and skin. Bleackley suggests that tumours with low expression of the receptor would not take up granzyme B, and they would therefore be refractory to killer T cells. He predicts, “If there is some way of re-establishing expression of the receptor in the tumours, the sensitivity to killers would return”.
Courtesy of B Motyka
Canadian researchers uncover vital new clues in cancer
Laser scanning confocal microscope image of a murine fibroblast line (L cells) after incubation with fluorescently tagged granzyme B.
These findings could completely alter the way doctors treat cancer and lead to new treatments for autoimmune diseases such as diabetes and rheumatoid arthritis, as well as preventing rejection of transplanted organs. Pharmaceutical companies are expected to begin soon to search for compounds that either block or stimulate the mannose 6phosphate/insulin-like growth factor II receptor. Jamal Nasir
Breast reconstruction cannot exorcise phantom pain Phantom breast syndrome, unlike phantoms reported after loss of a limb, tends not to fade with time but may remain disturbing for years. The symptoms range from itching to intermittent shooting pains in the missing tissue. Under-reporting of the syndrome is suspected, though small surveys show that the majority of mastectomy patients experience phantom sensation and up to 40% suffer pain. Now, a larger study carried out by Raja and co-workers (John Hopkins Medical Institutions, Baltimore, USA), has shown that pain persists even after reconstructive surgery has restored the appearance of normality. At a recent meeting of the American Society of Anesthesiologists, Raja and colleagues presented the analysis of questionnaires completed by 279 of 504 women who had undergone 200
mastectomy over a 3-year period. Almost 50% of the women had reconstructive surgery, two thirds of these by muscle transfer from the abdominal wall (TRAM-flaps), with the remainder opting for silicone or saline implants. Throbbing, unpleasant itching, pins and needles, and pressure were reported by 109 women, and phantom pain was reported by 87, with no significant differences in pain occurrence, intensity, or duration in relation to reconstructive surgery. In all, 31% of the mastectomy-only group and 35% of the reconstructive-surgery group reported pain. The true problem lies in the brain. The existence of pain before mastectomy is the strongest risk factor, which suggests that pain pathways have been reinforced. After mastectomy, cortical areas no longer sense the amputated breast, and take
stimuli from the surrounding shoulder. This information conflicts with vision, sense of balance, and muscle proprioception, and in a cortex already primed by previous pain, the result can be severe. Current treatments include creams based on capsaicin to provide temporary relief. In future, we may be able to attack the problem at its root. “I am optimistic,” says John Harris (University of Otago Medical School, Dunedin, New Zealand), who uses the cortical basis of pathological pain to develop treatments, “that therapeutic regimens, perhaps quite simple ones involving touch, manipulation, and visual observation of the reconstructed breast and surrounding tissues, might be effective”. For now, surgery results may fool the eye but the brain is not so easily persuaded. Janet Stephenson
THE LANCET Oncology Vol 1 December 2000
For personal use only. Not to be reproduced without permission of The Lancet.