CHAPTER 1
An Introduction to Cancer Cell Biology and Genetics

IN BRIEF

I find it impossible to describe how targeted cancer treatments work without mentioning what it is they target. And when I try to explain what it is they target, I find myself going back to the beginning and explaining where cancers come from, what faults they contain, and why they behave as they do. And, to explain that, I need to explain concepts such as DNA damage, oncogenes, tumor suppressor genes, and the hallmarks of cancer cells.

In recent years, we’ve also made great progress in using a patient’s immune system to treat cancer using immunotherapy. When explaining how immunotherapies work, I find it useful to offer at least a brief description of our immune system and the ways in which cancer cells and white blood cells interact. Armed with this knowledge, various strategies to use the immune system to destroy cancer cells begin to make sense.

In this chapter, my goal is to bring together much of this background knowledge. I hope it will provide you with a useful foundation that enables you to understand individual targeted therapies and immunotherapies that I mention in later chapters.

First, I run through the causes and consequences of DNA mutations in cells. I describe how even just a handful of mutations can force a healthy cell to become a cancer cell.

I also describe the cancer microenvironment – the cells and structures that cancer cells live alongside, including white blood cells of our immune system. Cancer cells have the ability to exploit their local environment and, in many instances, manipulate it. I explain what impact this has when doctors come to treat people with the disease.

In addition, I tackle topics such as genome instability and intratumoral heterogeneity. Perhaps these are topics that right now don’t mean anything to you, and you’re unsure of why you need to know about them. But it’s only through understanding these concepts that you can appreciate the limitations of targeted (and standard) cancer treatments and grasp the potential of immunotherapy. It is also important to understand why cancer spreads and how cancers evolve and change over time.

I then turn my attention to the unique properties of hematological cancers. I describe some of the types of mutation that drive their behavior and talk about why these mutations occur. I also explain their greater vulnerability to immunotherapy compared to solid tumors.

Finally, I wrap up the chapter with a brief overview of why cancer is so difficult to treat successfully and why so many people currently cannot be cured.

1.1 INTRODUCTION

This book is about the science that lies behind targeted cancer treatments and cancer immunotherapies. Almost without exception, these treatments work by attaching to, or blocking the actions of, proteins. So, to understand these treatments, it’s first of all essential to understand what proteins are, how they work, and how the proteins found inside and on the surface of cancer cells differ from their healthy counterparts.

For this to make sense to you, I need to explain the different types of DNA damage that cancer cells contain, because a cell’s DNA is its instruction manual telling it how to make proteins. If we know what DNA damage a cell contains, this will tell us what faulty proteins it’s making. And if we know what faulty proteins it’s making, we will have a better idea of which treatments might work against it.

So, this chapter contains lots of information about cancer cells, DNA, and proteins. However, even in this chapter, I’ve made some assumptions about what you do and don’t know. For example, I’ve assumed that you have a rough idea of what DNA is and how cells use their DNA to make proteins. If you’re not familiar with these concepts, I would recommend first taking a look at the Appendix, which contains a list of reading materials about cells, DNA, chromosomes, genes, and proteins. When you’ve had a look at that, you’ll be ready to read further.

This chapter doesn’t exclusively focus on individual cancer cells and their faults.

AbbreviationCancer cells don’t live alone, nor are tumors a homogenous mass of identical cancer cells. Instead, cancer cells live among other types of cells, such as fibroblasts, fat cells, and numerous types of white blood cells. This composition changes over time and also in response to treatment. In addition, cancer cells themselves evolve and change over time, and this has an enormous impact on the effectiveness, or not, of many treatments.

In this chapter, I’ll also provide you with some background information about how cancer cells relate to, and influence, our immune system. Why it is, for example, that in some people their immune system reacts strongly against their cancer cells, while in another person their immune system seems to essentially shrug its shoulders and carry on as normal. I’ll also pay special attention to T lymphocytes (T cells), which are at the heart of many different forms of immunotherapy.

Some of the information in this chapter is relevant to all cancers, wherever they occur in the body and whatever type of cell they developed from. However, there are some features of hematological cancers (such as leukemias and lymphomas) that set them apart from solid tumors like breast or bowel cancer. Some of this difference comes down to the mutations that drive hematological cancers, but some of it is due to their accessibility to drugs, and to healthy white blood cells.

Along with the chapter that follows (which is all about the two main groups of cancer treatments in this book: monoclonal antibodies and kinase inhibitors), this chapter hopefully provides you with all the background information you need to make sense of the rest of this book.

1.2 DNA DAMAGE IS THE CAUSE OF EVERY CANCER

Our cells’ DNA is essentially a huge instruction manual telling our cells what proteins to make, how to make them, when to make them, what to do with them, and when to destroy them. In turn, the proteins our cells make dictate their behavior. For this reason, if you damage a cell’s DNA, it is likely to make the wrong, or damaged, versions of proteins, leading to abnormal behavior (see Figure 1.1).

Cancer starts to develop when a single cell accumulates DNA damage to several important genes. This damage causes the cell to make faulty proteins that force it to behave abnormally. To result in cancer, the cell also needs to overcome whatever hostile forces are exerted by its environment and by neighboring cells. Thankfully, this normally doesn’t happen. Instead, a cell that finds its DNA damaged usually tries to repair the damage, or it self‐destructs through a process called apoptosis.1Or, if the cell doesn’t kill itself, it’s usually kept in check by its environment or destroyed by white blood cells. But, if a damaged cell survives, and if it avoids or overcomes its hostile neighbors, it might ultimately multiply and cause us to develop cancer.

Figure 1.1 Gene mutations cause the production of faulty proteins. Chromosomes are long lengths of DNA found inside the nucleus of each cell. Within our chromosomes are regions of DNA called genes. These are stretches of DNA that contain the instructions to make proteins. If a gene is affected by a mutation (represented by a lightning bolt), the cell might then make a faulty protein. In this example, the faulty protein is a cell surface receptor that gives the cell a continuous signal to grow and multiply.

Over the past 40 years or so, scientists have been gradually uncovering which gene mutations cause cancer. Genes only take up about 1%–2% or so of our cells’ total DNA, so it’s this DNA they have focused on [1]. (What exactly the rest of our cells’ DNA is for is a matter of continued debate among scientists.)

Box 1.1 The names of genes and their proteins

As you read this book, you might notice that protein names are written normally but that gene names are written in italics. For example, the HER2 gene contains the instructions for making HER2 protein. You might also notice that sometimes the gene and the protein have different names. An example of this is the TP53 gene, which contains the instructions for making a protein called p53. It’s also possible for a gene to contain the instructions for making more than one protein. For instance, the CDKN2A gene (sometimes referred to as the CDKN2A locus) contains the instructions for making several proteins, two of which are called p16INK4a and p14ARF.

To add to the confusion, some genes and proteins have more than one name. For example, the HER2 gene is also called ERBB2 and NEU. The reasons behind the various names often have a lot to do with what organism or group of cells the gene/protein was discovered in; if it’s similar to another gene/protein that has already been discovered; what role the gene/protein is thought to play in the cells or organism it was found in; and whether or not abnormalities in the gene/protein cause disease. For example, HER2 stands for “human epidermal growth factor receptor‐2,” because...