What is cancer?
Cancer involves the uncontrolled expansion of cells harboring harmful genetic defects as a result of deleterious hereditary and/or environmental effects (Figure 1).
In the United States alone, cancer is the second leading cause of death. The American Cancer Society estimates that in 2017, approximately 1.6 million new cases of cancer will be diagnosed and over 600,000 Americans will die from cancer-related causes. Cancer is primarily caused by deleterious mutations in special types of genes, which are referred to as “drivers” of cancer. Every “driver” falls into one of three categories: 1.) tumor suppressor genes, 2.) proto-oncogenes, or 3.) DNA repair genes. The nature of these genetic drivers explains why cancer is so difficult to cure.
Cancer cells rapidly divide, evade death, and “short-circuit” the body’s immune defenses
Mutations in tumor suppressors or proto-oncogenes confer cells with the ability to rapidly divide. As a result, cancer cells can quickly expand from a single cell into a large tumor in a short period of time, which is highly problematic from a diagnostic standpoint. Moreover, mutations in proto-oncogenes suppress the tendency of cancer cells to undergo a controlled death program after they have divided a specific number of times. This inhibition of cell death allows cancer cells to survive for much longer periods of time than a healthy cell. Furthermore, cancer cells frequently harbor deleterious mutations that make them “invisible” to the body’s immune system. Ultimately, the ability to rapidly divide and evade destruction allows individual cancer cells to migrate away from the primary tumor and quickly establish new tumors elsewhere in the body (a deadly process termed “metastasis”).
Tumors are composed of heterogeneous cancer cells that evolve resistance to therapeutics
Mutations in the third type of cancer driver—DNA repair genes—are another reason why cancer is so difficult to cure. DNA repair genes fix breaks in the DNA helix and correct any mutations that occur over the life of a cell. However, when a DNA repair gene is rendered non-functional, many mutations begin to accrue in individual cancer cells. Thus, the cancer cells within a tumor can be highly heterogeneous, possessing different compositions of mutations. Furthermore, the composition of mutated cells inside a tumor can be highly dynamic: it changes dramatically over time (Figure 2).
Physicians and scientists refer to this phenomenon as cancer cell evolution. This is extremely problematic because cancer cells can easily evolve resistance to therapeutics, much like bacteria evolve resistance to antibiotics. Thus, a drug designed to target one type of cancer cell harboring a particular mutation will effectively kill those cells, while leaving behind other cancer cells containing different sets of mutations. The resistant cancer cells will simply repopulate the tumor, ultimately requiring an entirely different therapeutic approach than the first (Figure 3).
Cancer is not a single disease
Cancer is also difficult to treat because the term “cancer” does not actually refer to a single disease. Instead, it is a collection of over 200 different types of diseases, all of which have different genetic causes. For example, next-gen DNA sequencing has already identified over 500 different genes implicated in a variety of different types of human cancers. Additionally, as alluded to earlier, a single patient can have a tumor composed of many genetically heterogeneous cancer cells. To complicate matters further, many of these genetic changes are not simple mutations in a single DNA base pair. Instead, genomic sequencing projects that assembled entire cancer genomes (such as early work that sequenced the first prostate cancer genomes) have revealed that many cancers are characterized by diverse chromosomal rearrangements. These rearrangements result in complex genetic regulatory interactions that are difficult to predict and develop targeted therapies against. Additionally, emerging research is now showing that cancer genomes harbor various types of defects that do not even involve DNA mutations, termed “epigenetic defects.” These epigenetic defects include abnormal biochemical alterations to the backbone of the DNA helix or to the special proteins around which DNA is wrapped (called histones). These epigenetic modifications subsequently have profound and (presently) highly unpredictable effects on gene expression throughout the genome.
The comprehensive cataloging of defects in cancer genomes may prove key to curing cancer
Cumulatively, it is this substantial complexity underpinning cancer biology that has, thus far, precluded the development a one-size-fits all cancer cure. Ultimately, it is difficult to treat a disease for which we do not fully understand its basic mechanisms. Thus, the development of better treatments—and possibly even cures—for cancer presently hinge on the systematic cataloging of the vast array of defects that occur in these deadly cell types during tumor progression. These foundational efforts promise to leave the scientific community better positioned to identify potentially key therapeutic “nodes” for improved drug targeting in the future.