Smoking Out Skin Cancer; Evolution in Action; Colon Cancer Resistance Found in Traveler's Diarrhea

Front Page | Smoking Out Skin Cancer; Evolution in Action; Colon Cancer Resistance Found in Traveler's Diarrhea Anne Macnamara Ah, the Irony: Colon Cancer Resistance Found in Traveler's Diarrhea Put the Imodium away, fly to an exotic location, and please drink the water. A new study--prompted by a manuscript outline on a dinner napkin--links resistance to colon cancer with "travelers' diarrhea" (G.M. Pitari et al., "Bacterial enterotoxins are associated with resistance to colon cancer," Proc Nat Acad Sci, 100:2695-9, March 4, 2003). Although undeveloped countries with poor sanitation have the highest risk of diarrheal disease, they also have the lowest incidence of colorectal cancer. Researchers found that a heat-stable enterotoxin, secreted from multiple bacteria, binds to the guanyl cyclase C (GC-C) receptor expressed exclusively on the surface of intestinal epithelial cells. "We wanted to elaborate the signaling mechanism that leads from GC-C receptor-ligand interaction to the suppression of proliferation previously observed in colorectal cancer cells," says Scott Waldman, clinical pharmacologist at Thomas Jefferson University, Philadelphia. GC-C binding signals "an intracellular catalytic domain that takes GTP and converts it to cyclic GMP," explains Waldman. "Then cGMP activates cyclic nucleotide gated channels (CNGC) on the surface, allowing calcium flow from outside to inside the cell." A dinner discussion between Haldman and electrophysiologist Andre Terzic of the Mayo Clinic, Rochester, Minn., resulted in Terzic and colleagues' use of patch clamping to measure accurately ion conductance. "The enterotoxins act by increasing membrane conductance for calcium, which turns on an antiproliferative pathway leading to resistance to colon cancer," says Terzic. Both chelation of extracellular calcium and specific inhibition of CNGCs prevented the antiproliferative response. --Susan Jenkins Smoking Out Skin Cancer Reprinted with permission from J Clin Invest, 111:43-50, January 2003. Chemicals similar to the active ingredient in marijuana appear to shrink tumors and rein in angiogenesis. Researchers in Madrid, building on findings that cannabinoids kill cancerous brain cells, studied the effect of cannabinoids on skin carcinomas in established murine models. Manuel Guzmán at the University of Madrid and others from the Power, Environmental, and Technological Research Center (CIEMAT) tested two synthetic cannabinoids: WIN-55,212-2, which affects cannabinoid receptors CB1 and CB2; and JWH-133, which acts only on CB2, the receptor not associated with marijuana's psychotropic effects. Both compounds caused apoptosis in vitro and in vivo, and cut the expression levels of major proangiogenic factors, including vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). Blood vessel counts were the same in cannabinoid-treated animals, but the vessel diameters in tumor tissue were de-creased (M.L. Casanova et al., "Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors," J Clin Invest, 111:43-50, January 2003). Both apoptotic and angiogenic effects appear to play a role, says Guzmán, though he admits it's a chicken-or-egg scenario. "We do not know what is first and what is most important--whether a cannabinoid first blocks angiogenesis and then cell death occurs because there is no irrigation of the tumor, or if it is the other way around." Further model work may piece together the actions of these synthetic molecules; Guzmán says a clinical trial is being conducted in which malignant brain tumors are treated with delta-9 tetrahydrocannibinol, marijuana's active component. Though no synthetic compounds have been tested for toxicity, CB2-specific agonists such as JWH-133 potentially could medicate with less controversy. --Brendan A. Maher Evolution in Action Courtesy of Christopher Majka In one of the first studies to show an evolutionary response to global warming, Canadian researchers reported that female red squirrels in southwest Yukon give birth, on average, 18 days earlier than their great-great-grandmothers did 10 years ago (D. Réale et al., "Genetic and plastic responses of a northern mammal to climate change," Proc R Soc Lond, published online, Feb. 13, 2003). The squirrels are not just acclimating annually to warmer weather; they are evolving in response to climate change. University of Alberta ecologist Stan Boutin has been studying these squirrels for 15 years, collecting a wealth of detailed data. The field season had been starting earlier every year, so Boutin suspected that something unusual was happening. But the change in reproductive timing wasn't obvious until Boutin's colleague, Denis Réale of McGill University, and graduate student Andrew McAdam analyzed the data using quantitative genetic techniques with which Boutin was not familiar. The statistics, says Boutin, revealed an "incredibly striking pattern." About 25% of the change was attributed to genetics. Other studies have shown behavioral responses to global warming. "My guess is that those changes aren't simply behavioral," says Boutin. "There's probably a genetic component .... They just haven't been able to tease it apart." McAdam plans to explore the molecular basis of the squirrels' evolutionary response. Boutin will keep collecting field data--he wants to know just how far evolution will go. --Leslie Pray

Smoking Out Skin Cancer; Evolution in Action; Colon Cancer Resistance Found in Traveler's Diarrhea

Front Page | Smoking Out Skin Cancer; Evolution in Action; Colon Cancer Resistance Found in Traveler's Diarrhea

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