Cancer I: Introduction

Introduction to Cancer On Dec. 23, 1971, President Richard M. Nixon signed into law a bill, The National Cancer Act that launched the "War on Cancer,", the goal of which was to sponsor a concerted effort to reduce the incidence of death from cancer in the United States dramatically. Since that time the U.S. has spent over a billion dollars a year, over $30 billion on the quest to identify the causes and develop cures for cancer. In 1984 the head of the National Cancer Institute predicted that by the year 2000 death rates from cancer would be half those of 1980. Do you know what has happened to cancer death rates in this country since 1971 as a result of those efforts? In the period between 1975 and 1990, the death rate from cancer rose 7% in the US, although it has fallen somewhat over the last decade; in other words, it’s just about where it was in 1984. Cancer is the second leading cause of death in the U.S. after? (heart disease). In contrast to the slow ups or downs in rate of death from cancer, the rate of death from heart disease has been falling steadily since the late 1960s, and has declined about a third since 1975. About half a million people die of cancer every year, and almost everyone has a family member who has been affected by cancer. Why the disparity in results for these two common killers? The following kinds of explanations have been offered, and there is likely to be some truth in all of them.
1. Cancer is a disease of the aged, and the US population is getting older on average.
2. Methods for diagnosing cancer are constantly improving, so some of the supposed increase may be artefactual; that is, people whose cancers were not previously being noticed are not being diagnosed with the disease--e.g MRI can reveal that what was thought to be a stroke is really a brain tumor.
3. New environmental factors, such as the dramatically increased use of pesticides and herbicides and synthetic chemicals since WW II, are contributing to the rate.
4. Behavioral patterns can affect the rate as well. What would you say if I told you that almost all the increase in the death rate from cancer is accounted for by an increase in the rate of death from lung cancer? (Show overhead). Most cases of lung cancer are thought to be caused by cigarette smoking, and malignant melanoma, a virulent form of skin cancer, is mostly caused by exposure to sunlight.
As these factoids suggest, the situation has not been improving much despite considerable effort and expense. As the next overhead indicates, however, the picture is not all dreary. Some forms of cancer, mostly cancers that are relatively uncommon, are much more curable than they used to be, and death rates from those are falling. Cancers of the testis, lymphoid cells (Hodgkin's disease), and cervix are much less deadly than they used to be because of better therapies (first two) or increased ability to detect the disease at an early state, when treatment is most effective (cervical cancer--Pap smears). But many other forms of cancer are killing more people than they were 20 years ago including melanoma, lung cancer in women, liver cancer, and many others, especially in people who are over 65.
What's going on? People aren't sure. If you look at the overall incidence of cancer and the rates of death from cancer, you see that less than half the people who are diagnosed with cancer on average actually die from the disease. Some of these statistics are misleading. For example less than 25% of men diagnosed with prostate cancer die of the disease. That's at least partly because prostate cancer is a disease of the elderly and because it isn't very fast growing. Thus many men with prostate cancer die from other causes before the cancer becomes life-threatening. So it isn't so much that there is a good cure for prostate cancer as it is that its a relatively slow growing cancer. On the other hand, the fact that breast cancer kills only about 25% of the women who develop it does reflect improvements in both early detection and treatment of the disease. (However, the overall incidence of the disease is increasing in this country, so death rates from it have stayed nearly constant. That is, a larger fraction of women who get the disease survive it but more and more women have been getting it).
From a cell biologist's point of view, the study of cancer offers a fascinating way to understand some of the fundamental processes of cells, including cell signaling, cell division, cell migration, and tissue formation. From a clinical point of view, the hope is that if we can understand the molecular changes that occur in cells that become cancerous, it may be possible to design rational therapies for them. At the moment the main treatments for cancer are cut, poison and burn--surgery, chemotherapy and radiation therapy. Surgery is fairly specific, but the others aren't. The idea in both chemotherapy and radiation therapy is to treat the cancerous cells with high doses of toxic substances-- drugs or radiation that kill rapidly dividing cells. However, these toxic treatments can't be delivered with precision to the cancerous cells, so they affect healthy cells as well. For example treating people with chemotherapeutic agents that are toxic to dividing cells kills not only fast growing tumors, but other fast growing cells such as those in the intestinal epithelium, which has many adverse effects on the patient. Similarly radiation cannot be targeted precisely at the cancerous tissue and so kills other nearby tissues as well. In some cases the cure is worse than the disease, and some cancer patients die from side effects of the therapy they are being given, rather than from the disease itself. So it would be ideal if we could identify some unique characteristic of cancer cells and use that characteristic to target them for treatments precisely. Let me give you an example of an effort along these lines. As you know mutations in the Ras gene are found in a large percentage of cancers, about 1/5. The Ras protein needs to associate with the membrane in order to function properly--one of it's main functions seems to be to bind Raf 1, a MAP kinase kinase kinase, to membranes. The way this happens is that Ras is posttranslationally modified by addition of a lipid, called a farnesyl group by the enzyme farnesyl transferase, which attaches the farnesyl group to a cysteine-aliphatic-aliphatic-anything sequence. Drug companies are trying to design inhibitors of the farnesyl transferase that get into cells and reduce the farnesylation and thus the activity of Ras. That's the idea, and one of the motivations for spending $30 billion on the cancer fight. So perhaps better therapies are around the corner, though cancer researchers have been promising them since I was knee high to a grasshopper.
So what is cancer? It's the name applied to a collection of diseases all of which are characterized by uncontrolled growth of cells and sometimes by invasiveness of the cells into regions of the body different from the regions in which they originated--so called malignant tumors. But it's misleading to think of cancer as one disease; rather it's a group of diseases with a common feature. Different cancers generally reflect the characteristics of the tissues in which they arose. Most cancers are cancers of epithelial tissue (overhead) because those tissues are the ones that divide most rapidly in adults, and because mutations arise most frequently during the process of DNA replication, epithelial cells are the ones most likely to incur mutations and to pass them on to progeny. (A mutation in a nerve cell is an isolated event, because normally it isn't a dividing cell.)
I just briefly want to summarize some cancer phenomenology, which is well covered by Alberts et al., and then next time we'll begin to discuss some of remarkable progress that's been made in the last 20 years in understanding the molecule basis of cancer. (That understanding hasn't paid off yet in a reduction in cancer deaths, of course).
1. Cancers are probably mostly clonal in origin--that is they derive from single abnormal cells that begin to grow so quickly that they become tumors.
2. Most cancers seem to be caused by mutations--i.e., by changes in the base sequence of DNA.
3. It probably requires several mutations to make a cell cancerous, not just one .
4. Thus, mutations that affect the rate of mutation are likely to cause cancer. One recently discovered type of cancer involved a mutation in a DNA repair enzyme, which was inactivated. Thus, the cells with this mutation were more likely to get other mutations, and to develop cancer as a result.
5. Cancer is a kind of natural selection. Cells that divide more rapidly than others can outcompete the others, just as organisms that reproduce more effectively than others become the most prevalent in a population.
6. Thus, cancer often involves successively more malignant cells originating from cells that are abnormal but not so malignant. I.e., in the population of cancer cells, some acquire additional mutations that allow them to grow more rapidly as time goes on, and these replace the other cancer cells and so on. This is seen clinically as a tendency for cancers to become more aggressive and deadly with time if they are untreated.
7. Treatments themselves can drive the evolution of cancer cells. Those cells that are most resistant to the chemotherapeutic agent are more likely to survive, and if they do, their descendants will be more resistant to the drug than the original population. Suppose that a chemotherapeutic drug can kill 99.9% (999 out of a thousand) of cancerous cells. By the time that a cancer is detected it is usually between 100 million and a billion cells (between 5 and 11 mm diameter). That means that even if 99.9% are killed there are somewhere between 100,000 and a million survivors. If these are the cells that are resistant to the therapeutic drug, then when they grow back, the drug will be ineffective with them. This is also often seen in clinical practice; recurrent cancers are much more difficult to treat than the original cancer.
8. Most cancers probably have environmental causes--such a stuff in foods, tobacco smoke, alcohol, etc. (More than 2 drinks per day--a recent study says more than one-- increases one's chances of dying of cancer). Most of these environmental carcinogens are mutagens--they increase the rate of mutation of human genes. The fact that different kinds of cancers can vary in frequency by as much as two orders of magnitude in different populations suggests strongly that there are local environmental causes.
9. Cancer can probably result both from mutations that allow cells to divide inappropriately and from mutations that prevent a cell from dying when it should. Cells have a detection system that picks up mutations and prevents cell division until the damage is repaired. If the repair doesn't occur within a certain amount of time, the cell can self destruct. Mutations that inactivate this suicide program allow defective cells to survive and become cancerous.
10. Most cancers are metastatic. And this makes them much more deadly than they would be if they were simply fast growing well localized masses of cells.
Neoplastic means growing faster than normal. All cancers are neoplastic; that’s simply the definition of cancer--cells growing abnormally rapidly. Most cancers are malignant--i.e., invasive. Non-invasive tumors (abnormal lumps of cells) are called benign. Invasive (metastatic) tumors are able to spread from their site of origin throughout the body, and thus cause much more harm. They are also much more difficult to find and detect.