Chapter 8 Chapter 8 The colon: an object of study in cancer development

The human intestine is a fertile ground for cancer.But that hasn't always been the case in human history, or at least colon cancer wasn't a common cause of death until recently.Two things have changed in modern society.Human life spans are now much longer than ever before.By the middle of the 20th century, many people had lived to the age of 70 or 80, the high incidence age of colon cancer.A century ago, few people lived to the age at which colon cancer developed.Our diets have also shifted from grain- and vegetable-based to increasingly heavy on meat and lots of fat.From the epidemiological survey results, we can clearly see the impact of dietary structure on humans: residents in some parts of Africa eat almost only vegetables and grains, and the incidence of colon cancer among them is only one-tenth of that in the West.

By the middle of this century, the incidence of colon cancer in the United States has risen sharply due to two factors: increasing life expectancy and changing dietary patterns.For researchers trying to understand the developmental history of a particular human tumor, the colon is a fascinating place to be.In the United States, the incidence of tumors in many other organs is only a few hundred or a few thousand cases per year.Colon cancer, by contrast, is plentiful—more than 100,000 new cases a year. The colon also has a unique feature. Unlike most other internal organs that are prone to cancer, the colon is easy to understand.A colonoscope—a flexible, optical catheter inserted through the rectum—gains a direct view of the cells lining the lumen of the colon.By the late 1980s, after millions of normal and cancerous colon investigations, a wealth of data had accumulated on how this complex tissue becomes diseased.

The cells that make up the normal colonic epithelium -- the layer of cells that line the large intestine -- typically replace rapidly.Epithelial cells form, mature, and then fall off in the lumen of the colon, a typical process that takes only two or three days from start to finish.Such rapid turnover means that these cells have a short effective lifespan, perhaps because they are vulnerable to the contents of the gut—digestion and the colon's plentiful bacteria.In effect, the lining of the gut is constantly taking short-lived cells from the line of fire and replacing them with new ones.This prevents an excess of defective, damaged cells from accumulating, including cells in which growth-control genes have mutated.

Although the gut wall is constantly being replaced, its tissue structure as a whole usually remains very stable and in good shape.The overall structure of the intestinal wall observed in the colonoscope has been carefully cared for during the lifetime of its owner.But in some people, the structure of the bowel wall breaks down and abnormal tissue develops.These abnormalities range from normal-looking excess cells (hyperplasia), to clusters of cells that already have some (but not all) characteristics of cancer cells (dysplasia), and abnormally developed protrusions of the colon called adenomas and polyps wall of cell clusters.

The extreme of change is overt cancerous growth (neoplasia).Like all epithelial carcinogenesis, they are considered cancers, but they manifest in different ways.Some are relatively stable and set up camp on the spot; while others invade the muscle layer of the intestinal wall and even send troops to colonize adjacent organs. The liver is their new continent. This series of progressive lesion sequences is not only a shortcut to arrange complex descriptive information.It also contains an important biological fact: the development of colon cancer goes through a series of steps, normal cells and tissues go through gradual aberrations, starting from completely normal and ending with high degree of cancer.

This sequence of progressive changes echoes our previously described theme that tumors are the end product of long-term, multistage development of genetic events.Perhaps the various precancerous growths in the wall of the colon are just a halfway point on its way from completely normal to completely cancerous.If the inferences are correct, malignant tumors can only arise from precancerous growths that are already abnormal, not directly from normal tissue. As promising as this insight is, it may, like many theories of the origin of cancer, be a simplistic consideration, an attempt to explain a complex phenomenon by virtue of a simple underlying mechanism.In fact, another view can explain the different types of growths in the colon, where the normal colon wall is making strides to transform into growths, some not too abnormal and some downright cancerous.Perhaps a normal cell occasionally jumps over the intermediate stage and takes a step forward to become a cancer cell.Colonoscopy fails to explain how normal and heterogeneous tissues are related to each other.

Analysis of the mutated genes in these neoplasms has shed light on this relationship.Bert Vogelstein of the Johns Hopkins School of Medicine in Baltimore started this work in the late 1990s.He analyzed biopsy specimens of several intestinal neoplasms, looking for obvious genetic abnormalities.The data he collected provides strong support for the idea that tumors evolve in small steps from a normal state to a malignant state; during the cancerous process, the number of mutated genes accumulated in the genome of colon cells is constantly increasing. Wokinstein found that during the development of neoplasms into malignant tumors, the 5th, 17th, and 18th pairs of chromosomes often lose diversity (heterozygosity).This observation suggests that there are tumor suppressor genes in these chromosomes, and the loss of each tumor suppressor gene is crucial for the onset of colon cancer.

The two copies of the MC tumor suppressor gene on chromosome 5 are already mutated in cells when the polyp is in its early, slightly abnormal growth stage.As the polyps proliferated, another mutated gene, the ras oncogene, appeared in the DNA of the cells.The polyps went one step further, and after losing a tumor suppressor gene that Wokinstein called DCC, the cells stood on the edge of a precipice.Finally, colon cancer cells harbored variants of the Hu53 tumor suppressor gene in addition to these three mutated forms. This observation demonstrates that cancer development is a multi-step complex process.It reinforces the idea that tumor development follows a Darwinian process, in which mutants are continually subjected to selection, in a cycle that leads to tumor formation.At the same time, the idea of ​​a step-by-step evolution of normal tissue into a full-fledged neoplasm is at its lowest point of credibility.

Not all tumors strictly followed this sequence of mutations.Other yet-to-be-discovered genes and gene variants will take their place.But this note does not weaken the dominant idea.Indeed, tumor formation depends on a series of mutations that, in cascade, produce rapidly expanding neoplasms and eventually cancer. Apparently, among the mutated sequences were tumor suppressor genes, but also at least one oncogene.While oncogenes are highly activated, tumor suppressor genes are inactivated.Let’s use the car analogy again: Cancer cells grow thanks to the gas pedal being pressed all the way down, and the brakes failing.

It is now necessary to revise the cooperative mode of the aforementioned oncogenes.As mentioned earlier, oncogenes alone cannot turn normal cells into tumor cells, but different combinations of oncogenes (such as ras and my c) can work together to induce cell transformation.It shows that cells must accumulate several mutated oncogenes on the road to canceration.In fact, few human tumors harbor multiple mutated oncogenes; and the example of colon cancer—one activated oncogene (such as ras) plus the inactivation of several tumor suppressor genes (Apc, Dcc, and p53)— Much more typical.Thus, cancer originates from the activation of oncogenes and the inactivation of tumor suppressor genes.cover

Like retinal glioma, colon cancer has a family history.In the United States, 1 percent of colon cancer cases arise from a genetic condition called familial polyposis.In affected families, where the mutated gene is passed down through generations, family members develop multiple polyps in the colon.Polyps number in the thousands and cover the wall of the large intestine. Although these polyps are benign and do not metastasize, it is clear that each of them has the potential, albeit unlikely, to develop into a malignancy.People with familial polyposis have so many polyps that sooner or later a polyp always turns into life-threatening colon cancer. The pattern of genetic transmission of susceptibility to polyposis from parent to offspring is very similar to that of retinal glioma.A defective form of a mutated tumor suppressor gene is passed on in sperm or eggs.Children who inherit the gene are destined to develop tumors in a specific target organ (in this case, the colon).As in retinoid gliomas, a cell in the target organ, which at some point loses the remaining intact copy of the tumor suppressor gene, begins to expand unchecked. This genetic mutation has already met us - it is C.In the sporadic cancers we described in the previous chapter, the inactivation of one copy of the gene was only the first step in the multistep developmental history of colon tumors.Since then, the cell has discarded another copy of the A and C genes on the road to canceration. Individuals who inherit a defective but c copy have already taken the initial step in the multi-step process of cancer.In all their colon cells, they had one copy of the mutated gene, so the cells could go straight to the next step—eliminating the remaining intact copy of the A and C genes.In these individuals, the process of forming polyps and eventually tumors is greatly accelerated. Familial polyposis and familial retinoid glioma thus greatly simplify our study of sporadic and familial cancers.Familial cancers are doomed at the moment of conception, while sporadic cancers are more common, arising from random genetic events that can occur throughout a person's lifetime.We can first unify the two types of cancer because they involve the same set of genes.Having mutated forms of them in germ cells (sperm or eggs) predisposes individuals to an innate predisposition to cancer; if these genes mutate due to random events in cells in the target organ, tumors form unstoppable, This condition accounts for 90% of all cancers in most human populations.