Comprehending Cancer Development

In this section you will learn:

  • Research provides our understanding of cancer biology, including its initiation, development, and progression.

  • Cancer is not one disease; it is a collection of diseases characterized by the uncontrolled growth of cells.

  • Changes in the genetic material in a normal cell underpin cancer initiation and development in most cases.

  • A cancer cell’s surroundings influence disease development and progression.

  • The most advanced stage of cancer, i.e., metastatic disease, accounts for most cancer-related deaths.

  • The more we know about the interplay between the individual factors influencing cancer biology, the more precisely we can prevent and treat cancer.

Discoveries across the breadth of biomedical research, from population science and basic research to translational and clinical research, have led to our current comprehension of how cancer arises and develops (see sidebar on What Is Basic Research and How Does It Drive Progress against Cancer?).

We have learned that cancer is a collection of diseases that arise due to uncontrolled cell multiplication. In adults, cell multiplication is a highly controlled process that occurs mostly to replenish cells that die due to normal wear and tear or damage from external factors. If the processes that control normal cell multiplication and lifespan go awry, cells start multiplying uncontrollably, fail to die when they should, and begin to accumulate. In body organs and tissues, the accumulating cells form masses called tumors, whereas in the blood or bone marrow they crowd out normal cells. Over time, some cancer cells invade local and distant tissues, a process termed metastasis, by entering the bloodstream or lymphatics, and form secondary tumors at remote sites. Most cancer-related deaths are due to metastasis.

Cancer Development: Influences Inside the Cell

The normal behavior of each cell in the human body is controlled by the genetic material within it. The genetic material comprises chains of deoxyribonucleic (DNA) units arranged in a particular order and packaged into condensed structures called chromosomes, inside the cell’s nucleus (see sidebar on Genetic and Epigenetic Control of Cell Function). The order of the DNA units as well as its three-dimensional structure dictates which protein and how much of it is made by each cell.

Alterations in the DNA sequence, referred to as mutations, can disrupt normal protein function; they are the leading cause of cancer development (see sidebar on Genetic Mutations). Cancer-associated mutations most commonly affect three types of genes: oncogenes, tumor suppressors, and DNA repair genes. Mutations in oncogenes promote cell multiplication while mutations in tumor suppressor and DNA repair genes directly or indirectly release the normal brakes that keep cell multiplication in check in healthy cells. Each person’s cancer has a unique combination of mutations, and as a cancer progresses, additional mutations accumulate. The number of cells within a growing tumor that carry a given mutation depends on when the mutation was acquired during tumor growth. Thus, even within the same tumor, different cancer cells often have different genetic mutations. This variation, or heterogeneity, within a tumor or between a primary and metastatic tumor is a leading cause of resistance to treatment and thereby disease progression.

Although 5 to 10 percent of cancer-causing mutations can be inherited (see Table 3), most are acquired over an individual’s lifetime due to errors arising during normal cell multiplication or as a result of environmental exposures or lifestyle factors (see sidebar on Sources of Genetic Mutations).

Not all mutations acquired by a cell lead to cancer. In fact, the identity, order, and speed at which a cell acquires mutations determine whether a cancer will develop and, if a cancer does develop, the length of time it takes to happen. The progressive nature of cancer provides distinct sites for medical intervention to prevent cancer, detect it early, or treat progressive disease. In general, the further a cancer has progressed, the harder it is to stop the chain of events that leads to the emergence of metastatic disease, which is the cause of most deaths from solid tumors.

In addition to genetic mutations, changes in the physical structure of DNA caused by modification of the DNA and the proteins associated with it, termed epigenetic modifications, are frequently detected in cancer cells (see sidebar on Genetic and Epigenetic Control of Cell Function). Epigenetic modifications regulate how and when our genes are turned “on” or “off” and can be made by specialized proteins that “add” or “erase” unique chemical modifications on DNA and/or histones (26). In contrast to genetic mutations, epigenetic changes are often reversible, providing an attractive opportunity for therapeutic intervention. Our understanding of the role of epigenetics in cancer is, however, still incomplete, and continued research is needed to reveal the real therapeutic potential of the cancer epigenome.

Cancer Development: Influences Outside the Cell

Cancer is primarily caused by the disruption of normal cellular functions through genetic and epigenetic changes. Once a tumor is initiated, however, complex interactions between cancer cells and their surrounding environment—known as the tumor microenvironment—can contribute to disease progression.

The tumor microenvironment is a specialized niche surrounding the cancer cells (see sidebar on Cancer Growth: Local and Global Influences). Bidirectional communication between cancer cells and the tumor microenvironment affect cell multiplication, tumor heterogeneity, and tumor metastasis (27, 28). Furthermore, the tumor microenvironment can shelter cancer cells from the effects of radiation, chemotherapy, and immunotherapy thereby rendering them resistant to treatment (29). Future studies are likely to identify additional cellular and molecular mechanisms by which the tumor microenvironment interacts with cancer cells and may help us develop new and improved therapeutics.

Cancer Development: Integrating Our Knowledge

Knowledge is our greatest strength in driving progress against cancer. Knowing “why” a cancer develops, will help us determine “how” to treat it. For example, comprehensive analyses of human cancer genomes over the past decade revealed several genetic changes associated with a variety of cancers. These discoveries led to the development of a series of therapeutics targeted to rectifying the cellular changes that arise due to the mutations.

We have also learned that each person’s cancer is unique, in part because it is influenced by a patient’s biological characteristics and lifestyle factors. As a result, we have seen a major shift in treatment from a “one size fits all” to a more personalized approach. Precision medicine aims to tailor each person’s health care to the prevention and/or treatment strategies most likely to be of benefit, sparing each person the cost of and potential harms from prevention interventions and/or treatments that are unlikely to benefit him or her (see Figure 3).

Over the past decade, we have made significant progress in how we understand and treat the complex group of diseases we call cancer. Nevertheless, our current knowledge of cancer-causing genetic, lifestyle, and environmental risks is incomplete and ongoing research will continue to uncover additional cellular and molecular alterations that lead to cancer development. An area of primary focus is understanding the biological basis for disparities in cancer incidence and outcomes among certain segments of the U.S. population (see sidebar on U.S. Cancer Health Disparities). Concerted efforts are needed from all sectors of the biomedical research community to ensure that scientific discoveries benefit the entire population.

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