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Lecture 2.7. Cancer and the Immune System

Plan:

Introduction

1. CANCER IS A CONTROL SYSTEM PROBLEM

2. CLASSIFICATION OF CANCER CELLS

3. IMMUNE SURVEILLANCE AGAINST CANCER

3.1. CTLs and spontaneous tumors

3.2. CTLs and cancerous blood cells

3.3. CTLs and virus-associated tumors

3.4. Immune surveillance by macrophages and NK cells

4. VACCINATION TO PREVENT VIRUSASSOCIATED CANCER

Introduction

In this lecture, we’re going to discuss how the immune system deals with cancer. This is a disease which will touch us all, either directly or indirectly. Because you may not have had a cancer course, I will begin by discussing some general properties of cancer cells. After all, it’s important to know the enemy.

1. Cancer is a control system problem

Cancer arises when multiple control systems within a single cell are corrupted. These control systems are of two basic types: systems that promote cell growth (proliferation), and safeguard systems that protect against “irresponsible” cell growth. When controlled properly, cell proliferation is a good thing. After all, an adult human is made up of trillions of cells, so a lot of proliferation must take place between the time we are a single, fertilized egg and the time we are full-grown. However, once a human reaches adulthood, most cell proliferation ceases. For example, when the cells in your kidney have proliferated to make that organ exactly the right size, kidney cells stop proliferating. On the other hand, skin cells and cells that line our body cavities (e.g., our intestines) must proliferate almost continuously to replenish cells that are lost as these surfaces are eroded by normal wear and tear. All this cell proliferation, from cradle to grave, must be carefully controlled to insure that the right amount of proliferation takes place at the right places in the body and at the right times.

Usually, the growth-promoting systems within our cells work just fine. However, occasionally one of these systems may malfunction, and a cell may begin to proliferate inappropriately. When this happens, that cell has taken the first step toward becoming a cancer cell. Because these growth-promoting systems are made up of proteins, malfunctions usually occur when a gene that specifies one of these proteins is mutated. A gene, which when mutated, can cause a cell to proliferate inappropriately is called a proto-oncogene. And the mutated version of such a gene is called an oncogene. The important point here is that uncontrolled cell growth can result when a normal cellular gene is mutated.

To protect against malfunctions in the control systems that promote cell proliferation, Mother Nature has equipped cells with internal safeguard systems. These safeguards also are composed of proteins, and they are of two general types: systems that help prevent mutations, and systems that deal with these mutations once they occur. For example, cells have a number of different repair systems that can fix damaged DNA, helping safeguard against mutations. These DNA repair systems are especially important, because mutations occur continuously in the DNA of all our cells. In fact, it is estimated that on average, each of our cells suffers about 25 000 mutational events every day. Fortunately, repair systems work nonstop, and if the DNA damage is relatively small, it can be repaired immediately as part of the “maintenance” repair program.

Sometimes, however, the maintenance repair systems may miss a mutation, especially when there are many mutations and the repair systems are overwhelmed. When this happens, a second type of safeguard system comes into play – one that monitors unrepaired mutations. If the mutations are not extensive, this safeguard system stops the cell from proliferating to give the repair systems more time to do their thing. However, if the genetic damage is severe, the safeguard system will trigger the cell to commit suicide, eliminating the possibility that it will become a cancer cell. One of the important components of this safeguard system is a protein called p53. Proteins like p53, which help safeguard against uncontrolled cell growth, are called tumor suppressors, and the genes that encode them are called antioncogenes or tumor suppressor genes.

Mutations in p53 have been detected in the majority of human tumors, and scientists have now created mice with mutant p53 genes. In contrast to normal mice, which rarely get cancer, mice that lack functional p53 proteins usually die of cancer before they are seven months old. So, if you are ever asked to give up one gene, don’t pick p53!

The take-home lesson is that every normal cell has both proto-oncogenes and tumor suppressor genes. Where things get dangerous is when proto-oncogenes are mutated, so that the cell proliferates inappropriately, and tumor suppressor genes are mutated so that the cell can’t defend itself against proto-oncogenes “gone wrong.” Indeed, cancer results when multiple control systems, both growth-promoting and safeguard, are corrupted within a single cell. It is estimated that between four and seven such mutations are required to produce most common cancers. This is the reason why cancer is a disease which generally strikes late in life: it usually takes a long time to accumulate the multiple mutations required to inappropriately activate growth-promoting systems and to disable safeguard systems.

Mutations that affect growth-promoting systems and safeguard systems can occur in any order. For example, one type of mutation that is especially insidious is a genetic alteration which disrupts a safeguard system involved in repairing mutated DNA. When this happens, the mutation rate in a cell can soar, making it much more likely that the cell will accrue the multiple mutations required to turn it into a cancer cell. This type of “mutation-accelerating” defect is found in many (perhaps all) cancer cells. Indeed, one of the hallmarks of a cancer cell is a genetically unstable condition in which cellular genes are constantly mutating.