A team of scientists at Children's Cancer Institute Australia for Medical Research (CCIA), led by Associate Professor Maria Kavallaris, discovered that the bIII-tubulin component of the cell's cytoskeleton could play an important role in resistance to a wide range of drugs used to treat lung, ovarian and breast cancers.
Advanced non-small cell lung carcinomas (NSCLC) account for more than 80 per cent of lung cancer cases. More than one million people are diagnosed with lung cancer every year, the most common cancer in the world and the leading cause of cancer deaths. Chemotherapy remains the most effective treatment option, involving a diverse range of drugs, often used in combination. However, the emergence of drug-resistant tumours in NSCLC means chemotherapy no longer holds the promise of a good outcome for many patients.
Increased expression of bIII-tubulin has been linked to drug resistance in NSCLC, ovarian and breast cancers. In the latest Cancer Research publication, Associate Professor Kavallaris and her team showed that blocking the expression of the bIII-tubulin gene in NSCLC cells led to an increase in their sensitivity to a range of chemotherapeutic drugs.
Our results strongly suggest that the bIII-tubulin component is responsible for protecting NSCLC cells from the action of key chemotherapeutic drugs, said Associate Professor Kavallaris.
This is the first scientific evidence for the broader implications of abnormal expression of this protein.
We now have new insight into a mechanism of drug resistance in NSCLC which has not previously been reported. This has important implications for improving the targeting and treatment of a number of cancers which are resistant to current chemotherapeutic drugs, said Associate Professor Kavallaris.
ccia.au/
Beneficial bacteria in the colon aid in digestion and extraction of nutrients from food. However, harmful microbes also reside in the intestine, so animals that harbor bacteria have evolved a boundary, or barrier, in the form of the intestinal lining to keep the dangerous bacteria from injuring the colon wall.
The key to maintaining this mucosal barrier, the scientists discovered, is the "peacekeeper" activity of T-bet in the dendritic cells of the intestine's immune system. When T-bet is at normal levels, the boundary - a kind of demilitarized zone - remains intact and prevents trouble from pathogenic bacteria. But if T-bet is insufficient, the dendritic cells overproduce a powerful chemical called TNF-alpha (tumor necrosis factor-alpha) that triggers inflammation and causes normal cells to die. In ulcerative colitis, the T-bet-related excess of TNF-alpha leads to the death of cells making up the epithelial barrier of the colon, enabling harmful bacteria to chronically inflame the intestinal wall.
The scientists bred strains of mice that lacked T-bet and showed that the resulting disease was virtually identical to human ulcerative colitis.
Moreover, the investigators demonstrated that female mice with the disease could transmit it to baby mice that had adequate levels of T-bet. (The scientists placed genetically normal infant mice with the sick foster mother on their day of birth.) Presumably, the flourishing colonies of colitis-causing bacteria were passed down from the sick mother to the fostered mice. The disease was even "horizontally" transmissible from T-bet-deficient adult mice with ulcerative colitis to other adults with normal T-bet, through fecal-oral and skin-to-skin contact.
Inflammatory bowel disease can be treated with antibody drugs that block TNF-alpha activity, though their toxicity limits their use. The researchers showed that such antibody drugs cured and also prevented ulcerative colitis in T-bet-deficient mice. However, they are pursuing other potential therapies, such as increasing T-bet levels in the immune cells, administering natural immunity-dampening cells called T-regulatory cells, or giving "probiotics" - healthful bacteria that can keep the harmful microbes under control.
hsph.harvard/