The subjects had all opted to skip conventional surgical or radiation treatment in favor of a "watchful waiting" approach. The researchers say it is too early to tell whether the lifestyle changes kept the cancer cells in check. But they say the study indicates that exercising, improving nutrition and limiting stress may prompt "profound" differences in the behavior of genes. Among them: some genes believed to be tumor suppressors turned on or became more active, whereas certain disease-promoting ones, including oncogenes (in the so-called RAS family that are implicated in both prostate and breast cancer), were down-regulated or switched off.
In 2000, 10 million people worldwide developed malignant tumors, and 6.2 million people with cancer died. By 2020, 15 million people could be afflicted, according to the World Cancer Report. How many of these people will die? Some kinds of cancer, such as of the skin or the breast, already have relatively high cure rates, and as techniques improve, those rates should get better. But former American Association of Cancer Research president Tom Curran, a neurobiologist at St. Jude’s Hospital in Memphis, says two research themes hold the promise of actually vanquishing cancer altogether. “The first theme is individuation; that is, an appreciation that cancer is many, many diseases,” he says. As researchers dig into the genetic basis of cancer, they will decode its signaling pathways—the chemical messages cancer cells send to other cells. “In the future, instead of telling someone, ‘You’ve got liver cancer,’ we may say to that person, ‘Your cancer is a defect in the ras pathway and in p53 signaling, so you need these compounds that are effective for those pathways."
It is now known that K-ras mutations occur long before the formation of the actual cancer. They form in the precancerous stages, within lesions termed PIN, or Pancreatic Intraepithelial Neoplasia. These are ducts with clones of early neoplastic cells which have not yet invaded through the duct wall. In reality, these lesions are among the most common neoplasms of humans, occurring in nearly a third of elderly people. They are often unfortunately called "hyperplasias", a term which implies the lack of neoplastic character. Indeed, a rough estimate suggests that less than 1% of the lesions ever become invasive, which is to say, become a cancer. Thus, in many respects, they are similar to the adenomas of the colon; nearly a third of people will develop adenomas, yet only a small proportion will progress to colon cancer. A major effort of the Kern laboratory is to determine which of the genetic changes in PIN mark the lesions at high risk for invasion. K-ras mutations are uncommon in the early forms of PIN, but are found in the majority of advanced lesions. PIN having K-ras mutations will probably develop in 10% of persons during life.
Mutations of the K-Ras gene occur in over 90% of pancreatic carcinomas. No other human tumor comes close in mutational frequency. The ras pathway is important in the transmission of growth-promoting signals from the cell surface receptors, eventually toward the nucleus where these signals affect the production and regulation of other key proteins. It is interesting that although most mutations in genes are expected to cause their inactivation, with the Ras genes the opposite happens - they become more active in signalling. This is because of the engineering design of the protein.
Researchers from several institutions, including the University of Texas M. D. Anderson Cancer Center and Arizona State University, applied a potent skin cancer-causing agent found in cigarette smoke to the skin of mice, some of which had been pretreated with avicins. The pretreated rodents were 60 and 40 percent less likely to develop benign papillomas (an early sign of progressing cancer), depending on how the cancer-causing agent was applied, and had far fewer tumors than their untreated counterparts. These animals showed a marked decrease in mutations of the H-ras gene, changes in chromosome number, DNA damage from oxidative chemicals and inflammation, as well.
Cancer develops in steps. In skin tumors the process can start with a change in a single gene, such as H-ras. Oxidizing chemicals such as hydrogen peroxide accumulate, causing more mutations and changes in chromosome number, while inflammation sets in. Eventually, apoptosis, orderly cell suicide, fails, and these altered cells cut loose. But if the brakes are put on this process early enough, cancer need never arise
The study of S. cerevisiae aging, and of the RAS genes in particular, may help to illuminate some of the features of brain aging related to metabolic control and stress resistance. However, the utility of these studies does not stop with the RAS genes. The human homolog of the yeast longevity gene, LAG1, is expressed in the brain. The LAG1 protein affects glycosylphosphatidylinositol-anchored protein transport. Glycosylphosphatidylinositol-anchored proteins include plasma membrane proteins, such as N-CAM, that are important in the development and function of the nervous system.
The genetics of aging in yeast is a well-developed discipline, with some 14 genes that influence longevity identified. The first genes implicated in yeast longevity were RAS1 and RAS2, the homologues of mammalian HRAS. The divergent roles of these two genes in determining yeast life span was later demonstrated. The pleiotropic effects of yeast RAS are well known. The role of RAS in metabolic control and in resistance to stress was instrumental in proposing the importance of these physiological mechanisms for aging and in their perceived interrelatedness, particularly given the emerging outlines of similar responses in other organisms.
Two trout ras genes expressed in liver differ from human c-Ha-ras and c-Ki-ras genes genes by 11-19 changes at third positions of codons with the first 100 nucleotides of exon 1. A recently described ras gene from goldfish also differs from human c-Ha-ras and c-Ki-ras genes by 13 and 19 nucleotides, respectively, within this same exon 1 region. Since all fish last shared a common ancestor with mammals about 400 million years ago, one expects all fish and mammallian ras genes to show about the same degree of divergence, especially because the changes allowed by selection within these ras exon 1 regions have been entirely silent... codon third-changes, which are known to accumulate at an average rate of 1% per million years in diverging bacterial as well as mammalian genes.
Although AFB1 [a potent food-borne hepatocarcinogen] is a potent genotoxin, its interaction with specific gene targets in human cancer has not been established. Among the possible targets are ras proto-onco-genes, which have been found to carry activating point mutations with variable frequency in many human cancers and in many tumors induced by chemical carcinogens in experimental animals. Point mutations in ras genes occur with very high frequency in some human cancers, such as pancreatic adenocarcinoma, but have appeared infrequently in the few human hepatic tumors so far examined.
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