Turned-off Cannabinoid Receptor Turns On Colorectal Tumor Growth

New preclinical research shows that cannabinoid cell surface receptor CB1 plays a tumor-suppressing role in human colorectal cancer, scientists report in the Aug. 1 edition of the journal Cancer Research. Endocannabinoid signaling is important to the normal functioning of the digestive system and has been shown to protect the colon against inflammation. Since chronic inflammation is a known risk factor for colorectal cancer, the researchers decided to look into the role of cannabinoid receptors in a mouse model of colon cancer.

Cannabinoids previously had been shown to kill cancer cells in lab experiments by inducing apoptosis - programmed cell death. The team confirmed the role of CB1 in apoptosis, showing that tumor cells with high CB1 expression were sensitive to apoptosis when treated by a cannabinoid agonist. Cell lines with silenced CB1 resisted cell death.

A series of experiments showed that CB1 increases cancer cell death by stifling a protein called survivin. Survivin is overexpressed in nearly every human tumor but is barely detectable in normal tissue, DuBois noted. Overexpression of survivin is associated with poor outcome and reduced apoptosis in colorectal cancer patients. The researchers pinpointed a cell signaling pathway by which activated CB1 cuts down survivin.

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Elevated Levels of Metabolites in CSF Play a Role in HIV Patients with CNS Damage

A team of scientists from The Scripps Research Institute found an increased concentration of certain metabolites in the cerebrospinal fluid (CSF) of monkeys with SIV-induced central nervous system (CNS) disease, a model for HIV patients with CNS damage.

The investigators used global metabolomics to assess the levels of metabolites in CSF before and after SIV-induced encephalitis appeared. They found elevated levels in four categories: carnitine, acyl-carnitines, fatty acids, and phospholipids. Consistent with this, the team reports, a protein known to be important in the generation of fatty acids was increased in the brains of monkeys with SIV-induced encephalitis.

The elevation in free fatty acids and lysophospholipids correlated with increased expression of specific phospholipases in the brains of animals with encephalitis, according to the researchers. One of these, phospholipase A2 isoenzyme, is capable of releasing a number of the fatty acids identified. It was expressed in different areas of the brain in conjunction with glial activation, rather than linked to regions of SIV infection and inflammation. The scientists hypothesize that this indicates widespread alterations in infected brains.

The investigators then went on to try to understand whether the metabolic changes were due to SIV infection or were related to neurological involvement and encephalitis. CSF was collected before infection and approximately six months after infection from animals that did not progress to encephalitis. They found no significant changes in metabolite levels in animals that lacked neurological symptoms. This shows, according to The Scripps team, that the metabolic changes observed in late-stage infection are specifically related to SIV-induced encephalitis.

More research is needed to determine the exact role of the higher level of each metabolite, the researchers note. They point out, though, that many of these metabolites are known to induce receptor signaling and thereby might be able to further modulate CNS function.

The findings are published in the June 2 issue of The Journal of Clinical Investigation.