CHAPTER 1
An Introduction to Cancer Cell Biology and Genetics

IN BRIEF

It is impossible to describe targeted cancer treatments 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 in order to explain that, I need explain concepts such as different types of DNA damage, oncogenes and tumor suppressor genes, and the hallmarks of cancer cells.

Hence, in this chapter, I provide an overview of the causes and consequences of DNA mutations in cells. And I describe how even just a handful of key 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 among. Cancer cells have the ability to exploit their microenvironment 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 genomic 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 the promise of immunotherapy. It is also important to understand why cancer spreads and how cancers evolve and change over time.

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 all about the science behind targeted cancer treatments. And, almost without exception, all targeted cancer treatments work by targeting proteins that are either inside or on the surface of cancer cells or the cells around them. So in order to explain how targeted cancer treatments work, I need to describe the proteins found in cancer cells and how they differ from those in healthy cells. In order to do this, 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 know which targeted treatments might work against it.

A general understanding of the DNA damage that cancer cells contain, and what impact this has on cancer cells, should help you make sense of why some treatments are applicable to some cancer patients and not others. It should also help you understand why it can be helpful to test a patient’s cancer cells for the presence or absence of various DNA mutations.

So this chapter is all about cancer cells, DNA, and proteins. And, along with the chapter that follows (which is all about the two main groups of targeted cancer treatments: monoclonal antibodies and kinase inhibitors), this chapter will hopefully provide you with all the background information you need to make sense of the rest of the book.

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. I’m also assuming that you know what proteins are and a bit about what some of them do. If you’re not familiar with these concepts, I would recommend first of all taking a look at the Appendix, which contains a list of reading material about cells, DNA, chromosomes, genes, and proteins. When you’ve had a look at that, you’ll be ready to read further.

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, you also end up with damaged proteins, leading to abnormal behavior.

A cancer starts to develop when a single cell accumulates DNA damage that causes it to make various faulty proteins that force it to behave abnormally. This normally doesn’t happen. A cell that finds its DNA is damaged usually either tries to repair the damage, or it self‐destructs through a process called apoptosis.1 But, if a cell doesn’t notice the damage and survives and later accumulates more damage, it might ultimately become a cancer cell.

Over the past 40 years or so, scientists have been gradually discovering what DNA damage cancer cells contain and how this affects their proteins. The scientists’ primary focus has been to study the DNA that contains the instructions to make proteins – our cells’ genes. This protein‐coding DNA only takes up about 1% or so of our cells’ total DNA [1]. (What exactly the other 99% of our cells’ DNA is for is a matter of continued debate among scientists.)

Through initiatives such as The Cancer Genome Atlas [2] and the International Cancer Genome Consortium [3], hundreds of scientists have amassed an incredible catalog of information about the thousands of different DNA mutations cancer cells contain [4]. They’ve also discovered that different types of cancer differ from one another in terms of the mutations they contain and the treatments they respond to. And as well as the differences, we know that important similarities can exist between cancers that arise in different organs. For example, some breast cancer patients may have tumors that overproduce2 a protein called HER2, as do the tumors of some patients with stomach cancer [5].

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 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 it’s similar in structure to HER1 (although we usually refer to HER1 as the EGF‐Receptor). HER2 is also called ErbB2 because a very similar gene, called Erb‐b, was discovered in a disease‐causing virus called the avian erythroblastosis virus. And HER2 is also called NEU because a faulty version of it can cause a cancer called neuroblastoma in rodents.

A final point to note is that gene names are often written in capital letters, whereas protein names aren’t. But this convention isn’t always adhered to.

Because there is lots to say about the DNA mutations in cancer cells, I’m going to split it up into different topics. First, I’ll talk about what causes the DNA mutations found in cancer cells (Section 1.2.1). Then I’ll describe what types of mutation occur (see Section 1.2.2), how the number of mutations in cancer cells varies (see Section 1.2.3), and which mutations have the greatest effect on cell behavior (see Section 1.2.4). Then I’ll talk about some of the most common gene mutations in cancer cells and what impact they have (Section 1.2.5).

Later in the chapter, we will look at the defining characteristics of cancer cells (Section 1.3), how cancer cells in a tumor can be genetically different from one another (Section 1.4); how they interact with and influence the non‐cancer cells that live alongside them (Section 1.5), and how they invade and spread (Section 1.6).

All of this information is gradually helping scientists create new, more targeted cancer treatments, which are the subject of the rest of this book.

1.2.1 Causes of DNA Mutations

There are many different reasons why our cells’ DNA gets damaged. Some of this damage is natural and unavoidable, whereas some of it is down to our lifestyle, behaviors, exposures, geographical location, and even...