Biology 166 Unsolved Problems in Cell Biology
Albert Harris
Cancer in One Easy Lesson
"Follow, Poet... follow right... to the bottom... of the night." W.H. Auden
1) The disease cancer results from a loss of control of growth and motility, usually resulting from somatic mutations, but sometimes resulting from virus proteins that block normal mechanisms of growth control, for example at cell cycle checkpoints.
2) Please notice that cancer cells do not grow or divide faster than normal cells, although many people believe that, and most forms of chemotherapy were designed on the assumption that they grow faster. Actually, what makes cells cancerous is the lack of control of cell growth, so that they keep on growing without limit, even if slowly. On the other hand, some kinds of cancer cells do grow quite rapidly, even if not faster than certain normal cell types, such as those in the bone marrow that constantly replace blood cells, and those in the intestinal lining and skin (including hair follicles) that constantly renew those structures. In one form of lymphoma, the abnormality has nothing to do with growth or division at all, but instead is a lack of apoptosis (programmed cell death), so that the cells accumulate without limit.
3) Benign versus malignant:When the growth of cells is uncontrolled, but the cells do not migrate or otherwise spread abnormally, and so remain together in a mass, they are said to be benign.Despite the usual connotations of the word benign, a benign tumor is not good for you - and can even be fatalif located in certain places like the brain, where it cannot be removed and where its growth alone can fatally damage indispensable tissues. When cells not only lack growth control but also move without control, in the sense of penetrating other tissues and otherwise spreading through the body, then they are said to be malignant. Lymphomas and leukemias inherently spread in this way, but vary widely in the degree to which they colonize bone marrow, lymph nodes etc.
Tumor versus cancer:The word tumor refers to a mass of (either) benign or malignant cells.
If they are malignant (i.e. invasive, capable of spreading), then the mass is a cancer.
Uncontrolled cell growth: --> benign tumor
Uncontrolled cell growth PLUS uncontrolled cell locomotion: --> malignant cancer
4) Metastasis: (plural, metastases): when cells spread from place to place within the body by invading blood vessels or lymphatics and being carried to new locations by the flow of the blood and lymph, this process is called metastasis. When cells colonize new locations by fluid transport, each of the new masses of cancerous cells is called "a metastasis". Less commonly, cells can also metastasize (that's the verb) by penetrating into other fluids, such as the peritoneal fluid or even the urine in the ureter, and are carried to new locations by these fluids instead of the blood or lymph.
5) Any cell type that is capable of division and locomotion is potentially capable of becoming cancerous. Although cancerous cells tend to be less well differentiated than normal cells, they almost always continue to have many of the differentiated characteristics of the cell type from which they were derived. For example, liver cancer cells still remain recognizable as liver cells (make liver enzymes, are shaped like liver cells, etc.), even after they may have metastasized to some other location in the body.
6) Carcinoma: a cancer derived from epithelial cells and having some of their morphological characteristics. About 80% of cases of human cancers are carcinomas.
The word adenocarcinoma refers to those with a glandular morphology.
7) Sarcoma: a cancer derived from mesenchymal cells, and having some of their morphological characteristics. Fewer than 5% of human cancer are sarcomas; but this percentage is higher in other species.
8) Leukemia: a cancer of one of the many kinds of white blood cells (even including lymphocytes), in which the percentage of these cells in the circulating blood rises greatly. About 28,000 new cases per year occur in this country. The most rapidly growing forms, acute childhood leukemia used to be invariably fatal within a few months, but are now the most curable by chemotherapy. Red Skelton's son and George Bush's daughter, Robin, died of acute childhood leukemia back in the 1950s, but could probably have now been cured with chemotherapy, which has now cured hundreds of thousands of children.
9) Lymphoma: a cancer of lymphocytes.Cancerous cells of this type usually accumulate in the lymph nodes and bone marrow, rather than circulating. There are B-cell lymphomas as well as T-cell lymphomas. The most common form is called Hodgkin's disease, affecting about 7,500 Americans per year, and is about 75% curable by chemotherapy. The other ten kinds are lumped together under the name "non-Hodgkin's Lymphoma" with about 35,000 new cases per year in this country . Many forms are curable by chemotherapy, or go into very long-term remission. Chancellor Hooker died of this.
10) Multiple myeloma is a cancer of relatively well differentiated lymphocytes, in which antibody light chains, or fragments of them are produced in considerable quantities, accumulating in the blood and urine and called "Bence-Jones proteins". The realization that these proteins are antibody fragments, accompanied by the determination of their amino acid sequences, was a crucial step in the history of immunology, and part of what convinced people that antibody specificity results from primary structure and that different antibodies are produced by different clones of lymphocytes. About 12,000 Americans per year die of this disease, of which one of the frequent symptoms is gradual erosion of the skeleton.
11) Teratomas, and teratocarcinomas: are suspected of being cancers of primordial germ cells. These tumors contain many different kinds of differentiated cell types. For example, it is not unusual for them to have brain or kidney cells on the inside, but have hair and/or teeth growing out of their surfaces. There are some special kinds that consist of just neural crest-derived cell types.
12) Neuroblastomas: It so happens that nerve cells never divide, or even synthesize any more DNA, once they have started to sprout axons and dendrites. So there are no cancers of nerve cells. Nevertheless, there is such a thing as a cancer of nerve cell precursors, and such cancers are called neuroblastomas (because a nerve cell precursor, a cell which has become determined to differentiate as a nerve cell, but hasn't actually differentiated yet, is called a neuroblast). There are neuroblastoma cell lines that you can grow in tissue culture; by changing their culture conditions, you can cause the cells to sprout axons, but then they can't grow any more. Sometimes neuroblastomas in children undergo spontaneous remission (self cure) because all the cells of the tumor differentiate to form what amounts to a gigantic abnormal ganglion. One approach to trying to treat this kind of cancer is to induce their differentiation.
There are some even rarer forms of cancer made up of precursors to muscle cells, including skeletal muscle myoblasts, which never make DNA once they fuse and become multinucleate.
13) Mortality: More than a million new cases of cancer per year occur in this country, with around a quarter of these being caused by smoking. In addition, there are around a half-million additional cases of skin cancer; but because these are usually detected earliest, and are also easiest to remove, skin cancers are almost always fully cured, to such a degree that they usually are no longer even included in the cancer statistics. Cigarettes kill slightly over 400,000 Americans per year (almost 10 times as many as by AIDS!), with many of these deaths due to heart disease and emphysema.
There are 150,000 new cases of breast cancer per year; 155,000 cases of colon and rectal cancer etc.
Your chances of getting cancer are about 1/4; your chances of dying of cancer are more than 1/5.
Cancers sometimes kill directly, for example by constricting some vital duct; but more often they kill by weakening the patient so much that fatal infections occur, or heart attacks, or strokes. In the case of weakened patients, the specific diseases involved are often the same ones that kill AIDS patients. Chemotherapy can itself also have fatal results, either directly, by weakening the immune system, or inducing another cancer!
14) Cure: Within living memory, tuberculosis used to be nearly incurable, killed more Americans per year than cancer, and had the same reputation as cancer for inexorable killing. Tuberculosis was what killed Anton Chekhov, Robert Louis Stevenson, the mathematician Riemann, all 4 Brontes, Chopin, Emerson, Kafka, Keats, D.H. Lawrence, Thoreau, Thomas Wolfe and George Orwell, most around age 40. A diagnosis of tuberculosis used to be an inexorable death sentence, but this disease then became almost completely curable with the drugs streptomycin and isoniazid. Unfortunately, Reagan's public health cutbacks (right-wing!) during the 1980s, combined with (left-wing!) soft-headedness toward forcing medical treatment and quarantine of "The Homeless", resulted in production of incurable strains of tuberculosis (because poor patients took too little of the drugs to kill all their germs, but enough to select for mutant germs less susceptible to these drugs). Tuberculosis now kills several thousand Americans per year & well over one million per year world-wide!
Will cancer ever become as curable as tuberculosis did? Maybe you can help make it so. Somewhere, there are weird little facts about cancer cells, that don't seem important because nobody has had the imagination to see how to take advantage of them to kill cancer cells while not harming normal cells. What is lacking is someone with the patience to collect such odd and useless facts, the imagination to figure out how to put these facts to use, the energy to develop methods for using these facts, all combined with the stubbornness not to give up along the way. This person might be you.
Since it is the cancer cell that is abnormal and defective, justice requires that it should die, not you. It is kind of ridiculous that developing the wrong kind of defectiveness in just one of your trillion-plus cells should be fatal to you. We need to find ways to make these kinds of cellular defectiveness fatal for the individual cells that possess them, instead of being fatal for your whole body! Keep this in mind: The goal is find drugs or other treatments that are more poisonous for cancer cells than they are for normal cells!
15)Current evidence indicates that the great majority of human cancers are caused by somatic mutations in certain specific genes. Genes with this property are called "oncogenes", and more than 70 kinds of oncogenes are now known. Based on the increasing frequency with which new methods for finding oncogenes have been finding the same ones over and over again, it is estimated there are upwards of 100 different kinds of oncogenes, total!
16) Somatic mutations, of course, are any changes in the genetic information in somatic cells (i.e. cells other than sperm or egg cell precursors). Somatic mutations are very common (millions or billions of them occur in a normal person); they are passed down only to the daughter cells of the cell undergoing the original mutation, and to their daughter's daughter cells, etc. thus forming a clone of genetically different cells within the body. Nearly all somatic mutations are harmless, either with no effect or making the affected cells slightly abnormal (defective but not dangerous).
But it is very, very dangerous to over-express or otherwise change that tiny minority of genes that code for the proteins whose function is to control cell growth. Cancer can result from single base changes in some of these genes, but is more frequently caused by gene duplications, deletions, or by translocations of genes from their normal location. Translocation to a position adjacent to the control regions (promoters and/or enhancers) of other genes can cause the translocated genes to be 'turned on' (transcribed) when they shouldn't be, or more than they should be. This causes most lymphomas.
17)Almost all cancers are believed to be clonal in the sense that all the cells of a given person's cancer are descended from just one original somatic cell that underwent a mutation in one (or more) oncogenes. The evidence includes such facts as that, in female mammals (where only one of the two X chromosomes is active in any given cell, with half the somatic cells having one of the Xs active and the other having the other X active) all the cells of any given tumor have the same active X. Likewise, cancers in chimeric animals (such as tetraparental mice) are found to contain only cells derived from one of the original embryos from which the animal was formed. In other words, cancer does not spread from cell to cell; the enlargement of tumors does not involve any kind of recruitment of previously normal cells; and it is not "catching".
18) Only certain genes can be mutated in ways which make the cells possessing them cancerous. Mutated genes that have this effect are called "cellular oncogenes", & the normal versions "proto-oncogenes".
19)Paradoxically, oncogenes were originally discovered because of their introduction into cells bycertain oncogenic viruses (i.e. viruses that can convert normal cells into cancerous cells). From a historical point of view, it is interesting to note that this outcome was contrary to the natural expectations of most people, such as those in government, who were thinking more along the lines of ordinary viral diseases. Although for some animals (including cats and chickens) communicable viruses really are major causes of cancer (so that anti-cancer vaccines have been developed), such cancers are rare in humans. Many cervical uterine cancers seem to result in part from sexually transmitted viruses; Burkitt's Lymphoma can be caused by the Epstein-Barr virus; "hairy cell leukemia" seems to be caused by a relative of HIV. But the great majority of human cancers seem to be due to somatic mutations. Nevertheless, the discovery of the nature of these mutations depended (in a historical and also a financial sense!) on studies of the molecular mechanisms by which oncogenic viruses cause cells to become cancerous. Without the familiar old simple-minded paradigm ("identify the germ, make a vaccine, etc.") to motivate them, politicians might not have been able to see the value of funding this viral research; and some of them (e.g. Pat Schroeder, John Dingell) have said that the money must have been wasted since the research didn't turn out the way they expected!
Although they are wrong to think the money was wasted, all too little thought has yet been given to the question of how to turn this knowledge into new kinds of treatments: how to design a drug that will selectively kill just those cells containing overactive oncogenes. Probably most cancer researchers think such efforts would be premature; but cancer patients wish they would get on with it. Maybe youwill do it!?
20)Oncogenic viruses have been discovered among at least seven of the dozens of taxonomic groups of viruses, with six of the 7 being DNA viruses. These six produce cancer by causing the over-expression of normal host oncogenes (in one of several ways, to be discussed below in #27). The 7th group were the retroviruses, the RNA viruses that copy their RNA genome into DNA. It turned out that (usually) these cause cancer by carrying copies of human genes that they had picked up from cells their ancestors had previously infected!!! . (Rather than being parts of the normal virus genome (such as gag, pol or env).
21)Oncogene-containing viruses provide a useful means for experimenters to transform large numbers of cells quickly and simultaneously, and with the same biochemical changes in each cell so as to make it practical to study the molecular nature of the changes produced. "Normal" human cancers result from the mutation of one or more proto-oncogenes to over-active forms; but researchers usually can't wait around for some rare mutation to change one cell at a time, especially since each transformed cell would usually differ in respect to which particular gene is over-active. Other methods for discovering oncogenes (besides using viruses) have been developed, including molecular mapping of whatever genes lie next to the reattachment points where chromosomes have broken and become spliced back to the wrong location (as in most lymphomas).
22)The very first virus to be discovered to cause cancer was the "Rous sarcoma virus" (RSV); this was discovered about 1910 by Peyton Rous, although he had to overcome so much skepticism that he did not receive the Nobel Prize for this discovery until 1966, when he was very old! This was also the first of the oncogenic viruses that was discovered to contain an extra gene (in addition to the virus' own genes) responsible for actually causing the transformation.