This section addresses the genetic and cellular processes that lead to cancer development, invasion, and metastasis.
The process of cancer development is known as carcinogenesis or tumor genesis. Cancer cells differ from normal cells in that they reproduce without normal restraints and have the potential to invade and colonize distant tissues. The combination of these features allows uncontrolled proliferation and development of a tumor, or neoplasm—a relentlessly growing mass of abnormal cells.1
As long as the neoplastic cells remain clustered together in a single mass, the tumor is said to be benign and is not considered cancer. In contrast, cells of malignant tumors do not have the cohesiveness of benign cells. They more easily break loose from the primary tumor mass, enter the bloodstream or lymphatic vessels, and form secondary tumors, called metastases, throughout the body.1
Dysregulation of the Cell Cycle
Cancer is a disorder of uncontrolled cell growth in which the regulatory processes for cell proliferation and cell death have been disrupted. This dysregulation of the cell cycle is the key feature that characterizes almost all malignant cells.1
The growth abnormality in cancer cells appears to result from:1
- Lack of appropriate control responses to signals that normally cause the cell to stop going through the cell cycle
- Lack of apoptosis in response to appropriate stimuli or stresses.
These abnormalities are caused by mutations of regulatory genes called proto-oncogenes and tumor suppressor genes. Proto-oncogenes stimulate cell cycling and, therefore, cell proliferation and survival. Mutated proto-oncogenes are called oncogenes because they promote uncontrolled cell growth that may lead to development of cancer.[i]
Apoptosis
Programmed cell death is an important mechanism for controlling cell proliferation. Loss of this mechanism is a key step in cancer development.1
Invasion and Metastasis
Invasion and metastasis are the two mechanisms by which cancer cells spread throughout the body. Invasion is the direct migration and penetration of cancer cells from the tumor’s primary site to neighboring tissues. Metastasis refers to the ability of cancer cells to spread from a primary tumor site to distant tissue sites.1 The development of metastases is a principal cause of cancer morbidity and mortality and is the major cause of cancer treatment failure.1,[ii]
The processes of carcinogenesis, invasion, and metastasis are caused by a series of gene mutations that provide cells with the potential for uncontrolled growth, penetration into surrounding tissues, and the ability to enter lymphatic and blood vessels and travel to and grow in unrelated tissues and organs.1 These processes are illustrated in Figure 5.
Figure 5: Mechanisms of Cancer Invasion and Metastasis
Carcinogenesis
As described earlier, genetic mutations occur that lead to uncontrolled growth and increased cell survival. As a result, a primary tumor mass develops in the tissue where the mutation originated.1
Vascularization
A tumor may exist for months to years without a blood supply of its own, obtaining oxygen and nutrients from its surroundings. As the tumor grows and central tumor cells become hypoxic, the tumor initiates angiogenesis to increase its blood supply.1
Vascularization of the cancer is associated with a dramatic increase in its potential to invade and metastasize. The increased numbers of blood vessels provide more opportunities for cancer cells to enter the circulation and spread to distant tissues. Additionally, tumor blood vessels are often defective, with leaky walls that make it easier for cancer cells to enter the vessels.1
Motility and Invasion
Additional genetic mutations provide the cancer cells with greater growth and invasion potential. Invasive cancer cells have decreased cell-cell adhesion and decreased attachment to the extracellular matrix, enhancing cancer cell motility and the ability of the cells to escape from the main tumor mass. These invasive cancer cells are able to move through tissue boundaries and can enter leaky tumor capillaries and thin-walled lymphatic vessels in surrounding tissues.1
Cancer Cell Transport and Arrest
Cancer cells that have entered the circulation are transported to other sites in the body. The cells stop in other organs by adhering to the capillary beds or by binding to the exposed basement membrane of cells.1
Extravasation and Secondary Growth
Arrested cancer cells leave the blood vessel by penetrating the blood vessel wall. The cells migrate into local tissues that are favorable for their continued growth and form secondary tumors. These tumors retain the appearance and characteristics of the original cancer.1
Factors Contributing to the Development of Cancer
The development of cancer generally involves many steps, each of which is governed by multiple factors. Some factors depend on the genetic constitution of the individual, while others are related to environmental factors and lifestyle. Genetic mutations that lead to cancer may occur randomly as a result of exposure to environmental carcinogens or DNA error or may be inherited mutations. Most adult cancers are sporadic, arising from an accumulation of spontaneous mutations throughout the lifetime of an individual.11
This section describes the genetic, physical, chemical, viral, and hormonal factors that may be related to the development of cancer.
Inherited Genetic Factors
An increased risk of cancer is associated with numerous genetic traits. Genetic predisposition to cancer is most often due to germline mutations—inherited genetic defects that are passed from parent to child in the germ cells at conception. However, inherited mutations play a role in only about 5 to 10 percent of all cancers.11
Familial Cancers
Familial cancers are cancers that occur in families more often than would be expected by chance. A small percentage of breast cancers and colorectal cancers are familial. Approximately 5 percent of all breast cancers are attributable to germline mutations of the BRCA1 and BRCA2 genes.[iii] Familial adenomatous polyposis (FAP) accounts for approximately 1 percent of colorectal carcinomas.[iv]
Several inherited multisystem syndromes are associated with a high risk of cancer, including neurofibromatosis, hereditary Wilm’s tumor, basal cell nevus syndrome, and Li-Fraumeni syndrome.[v] [Lindor/p1040/c1/Table 1] Li-Fraumeni syndrome involves germline mutations in p53, which result in increased rates of breast cancer, childhood soft tissue sarcomas, osteosarcoma, brain cancer, adrenal cortical carcinomas, and leukemia.15
Viruses
Certain types of viruses, sometimes referred to as oncoviruses, are capable of triggering the development of cancer. Both RNA viruses and DNA viruses have been associated with the development of cancer. RNA viruses, particularly retroviruses, are important causes of cancer. In the process of replication, retroviruses incorporate their genetic material into the host chromosomes, which can cause mutations of the host genome. Cancers associated with retroviruses include adult T cell leukemia (HTLV-1) and hepatocellular carcinoma (HBV and HCV).[vi]
Several DNA viruses induce cell growth by interfering with the tumor suppressor gene p53. Cancers associated with DNA viruses include hepatocellular carcinoma (HBV), anogenital and skin cancers (HPV), Burkitt’s lymphoma and Hodgkin’s disease (EBV), and Kaposi’s sarcoma (KSHV).16
Chemical Carcinogens
Exposure to chemical carcinogens can induce the development of cancer in humans. Susceptibility to cancer as a result of chemical exposure is influenced by individual genetic factors. Tobacco smoking is the most common cause of cancer and accounts for 30 percent of all cancer deaths. Tobacco smoking has been correlated with cancers of the lung, oral cavity, nasal cavity, lip, pharynx, larynx, esophagus, pancreas, cervix, ovary, kidney, bladder, stomach, and colorectum.[vii]
Numerous other chemicals are suspected carcinogens (Table 1).
|
Target Organ |
Agents |
|
Lung |
Tobacco smoke, arsenic, asbestos, crystalline silica, benzo[a]pyrene, beryllium, chromium compounds, |
|
Pleura |
Asbestos |
|
Oral cavity |
Tobacco smoke, alcoholic beverages, nickel compounds |
|
Esophagus |
Tobacco smoke, alcoholic beverages |
|
Gastric system |
Smoked, salted, and pickled foods |
|
Colon |
Heterocyclic amines, asbestos |
|
Liver |
Aflatoxin, vinyl chloride, tobacco smoke, alcoholic beverages, thorium dioxide |
|
Kidney |
Tobacco smoke, phenacetin |
|
Bladder |
Tobacco smoke, 4-aminobiphenyl, benzidine, phenacetin, 2-naphthylamine |
|
Prostate |
Cadmium |
|
Skin |
Arsenic, benzo[a]pyrene, coal tar and pitch, mineral oils, soots, cyclosporin A, psoralen plus ultraviolet A (PUVA) |
|
Bone marrow |
Benzene, tobacco smoke, ethylene oxide, antineoplastic agents, cyclosporin A |
Table 1: Known or Suspected Chemical Carcinogens and Target Organs[viii]
Physical Factors
Physical agents known to cause cancer in humans include:
- Ionizing radiation
- Ultraviolet light
Ionizing Radiation
Ionizing radiation consists of high-energy waves that are able to penetrate cells and can cause ionization in different parts of the cell. This tissue damage puts individuals at increased risk of developing cancer.[ix]
Exposure to ionizing radiation can come from both natural and human-made sources. Natural sources include background ionizing radiation from cosmic rays and radioactivity in the earth. Radon, a naturally occurring radioactive gas that emanates from the ground, has recently been recognized as a principle source of radiation exposure. Nuclear plant disasters such as the Chernobyl accident expose large numbers of people to radiation. Additionally, radiation used as a treatment for cancer increases the risk of secondary cancers.19
Certain tissues and cells are more susceptible to radiation than others. The organs most sensitive to radiation are the thyroid gland and the bone marrow. Radiation exposure causes increased risk for multiple myeloma, lymphoma, certain leukemias, and many solid tumor cancers, including breast cancer, thyroid cancer, bone cancer, and skin cancer.19
Ultraviolet Light
Exposure to ultraviolet (UV) light is responsible for increasing rates of skin cancer throughout the world, including basal cell carcinoma, squamous cell carcinoma, and melanoma. Skin cancer is most frequent in regions with high ambient solar radiation and in people exposed to sunlight as a result of their occupation. Chronic exposure to the sun is associated with risk for basal cell carcinoma and squamous cell carcinoma. In contrast, melanoma is less dependent on UV exposure.19
Hormonal Factors
Some circulating hormones may play a role in tumor promotion or progression. Hormones help some types of cancer cells to grow, such as breast cancer and prostate cancer.
[i] American Cancer Society. Oncogenes, tumor suppressor genes, and cancer.2011:1-8.
[ii] The Kuhn Lab. Circulating tumor cells (CTCs) for cancer diagnosis and prognosis. http://cancer.scripps.edu. 2013:1-2.
[iii] Son BH, Ahn SH, Kim SW, et al. Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: The Korean Hereditary Breast Cancer (KOHBRA) Study. Breast Cancer Res Treat. 2012; 133:1143-1152.
[iv] Haggar FA, Boushey RP. Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg. 2009; 22:191-197.
[v] Lindor NM, Mayo Familial Cancer Program. The concise handbook of family cancer syndromes. J National Cancer Inst. 1998; 90:1039-1071.
[vi] Rwazavian N. Can a virus cause cancer? Berkley Sci J. 2010; 14:19-22.
[vii] American Cancer Society. Tobacco and cancer. 2007:1-2.
[viii] Yuspa SH, Shields PG. Etiology of cancer: chemical factors. In: Devita, Hellman & Rosenberg’s Cancer: Principles & Practice of Oncology, 8th ed. 2008: Chapter 15.
[ix] American Cancer Society. Radiation exposure and cancer. 2006; 1-7.