Cancer is a deregulated multiplication of cells with the consequence of an abnormal increase of the cell number in particular organs. Initial stages of the developing cancer are usually confined to the organ of origin whereas advanced cancers grow beyond the tissue of origin. Advanced cancers invade the surrounding tissues that are initially connected to the primary cancer. At a later stage, they are distributed via the hematopoetic and lymphatic systems throughout the body where they can colonize in distant tissues and form metastasis. The development of cancers is thought to result from the damage of the cellular genome, either due to random endogenous mechanisms or caused by environmental influences.
Human cancer is probably as old as the human race. It is obvious that cancer did not suddenly start appearing after modernization or industrial revolution. The world’s oldest documented case of cancer comes from ancient Egypt, in 1500 BC. The details were recorded on a papyrus, documenting eight cases of tumors occurring on the breast. It was treated by cauterization, a method to destroy tissue with a hot instrument called “the fire drill.” It was also recorded that there was no treatment for the disease, only palliative treatment. The word cancer came from the father of medicine, Hippocrates, a Greek physician (460–370 BC). Hippocrates used the Greek words carcinos and carcinoma to describe tumors, thus calling cancer “karkinos.” The Greek terms actually were words to describe a crab, which Hippocrates thought a tumor resembled. Hippocrates believed that the body was composed of four fluids: blood, phlegm, yellow bile, and black bile. He believed that an excess of black bile in any given site in the body caused cancer. This was the general thought of the cause of cancer for the next 1,400 years. Autopsies done by Harvey in 1628 paved the way to learning more about human anatomy and physiology. By about the same time period, Gaspare Aselli discovered the lymphatic system, and this led to the end of the old theory of black bile as the cause of cancer. The new theory suggested that abnormalities in the lymph and lymphatic system as the primary cause of cancer. The lymph theory replaced Hippocrates’ black bile theory on the cause of cancer. The discovery of the lymph system gave new insight to what may cause cancer; it was believed that abnormalities in the lymphatic system was the cause. Other theories surfaced, such as cancer being caused by trauma, or by parasites, and it was thought that cancer may spread “like a liquid” (Bentekoe, 1687; Heinrich Vierling, personal communication). The belief that cancer was composed of fermenting and degenerating lymph fluid was predominant.
The discovery of the microscope by Leeuwenhoek in the late seventeenth century added momentum to the quest for the cause of cancer. By late nineteenth century, with the development of better microscopes to study cancer tissues, scientists gained more knowledge about the cancer process. It was not until the late nineteenth century that Rudolph Virchow, the founder of cellular pathology, recognized that cells, even cancerous cells, derived from other cells. The early twentieth century saw great progress in our understanding of microscopic structure and functioning of the living cells. Researchers pursued different theories to the origin of cancer, subjecting their hypotheses to systematic research and experimentation. John Hill first recognized an environmental cause from the dangers of tobacco use in 1761 and published a book “Cautions Against the Immoderate Use of Snuff.” Percivall Pott of London in 1775 described an occupational cancer of the scrotum in chimney sweeps caused by soot collecting under their scrotum. This led to identification of a number of occupational carcinogenic exposures and public health measures to reduce cancer risk. This was the beginning of understanding that there may be an environmental cause to certain cancers.
A virus causing cancer in chickens was identified in 1911 (Rous sarcoma virus). Existence of many chemical and physical carcinogens was conclusively identified during later part of the twentieth century. The later part of the twentieth century showed tremendous improvement in our understanding of the cellular mechanisms related to cell growth and division. The identification of transduction of oncogenes with the discovery of the SRC gene, the transforming gene of Rous sarcoma virus, led to formulating the oncogene concept of tumorigenesis and can be viewed as the birth of modern molecular understanding of cancer development. Subsequently, tumor suppressor genes were identified. Many genes that suppress or activate the cell growth and division are known to date, their number is ever growing. It is conceivable that in the end the confusing situation may arise to recognize that all genes of the human genome, in one way or another, take part in signaling normal or cancerous cellular growth.
Types of Genetic Damage
Point mutations resulting in the activation of a latent oncogenic potential of a cellular gene (e.g., RAS) or in the functional inactivation of a tumor suppressor gene by generating an intragenic stop codon that leads to premature translation termination with the consequence of an incomplete truncated protein (e.g., p53) or the failure for maintaining genomic stability (Mismatch repair genes in HNPCC).
Translocation, which is defined as an illegitimate recombination between nonhomologous chromosomes, the result being either a fusion protein (where recombination occurs between two different genes such as BCR-ABL in Chronic Myclogenous Leukemia) or in the disruption of normal gene regulation (where the regulatory region of a cellular gene is perturbed by the introduction of the distant genetic material such as MYC in Burkitt lymphoma (Epstein–Barr Virus)).
Viral insertion by the integration of viral DNA into the regulatory region of a cellular gene. This integration can occur after a virus has infected a cell. Viral insertion is well documented in animal tumors (HBV integration in the vicinity of MYCN in liver cancer in experimental animals; liver cancer, molecular biology).
Cancer in solid tissues (solid cancer) usually develops over long periods (often 20–30 years latency period) of time. An exception is solid cancers (such as neuroblastoma) in children, which often are diagnosed shortly after birth. Malignant cancers are characterized by their ability to develop metastasis (i.e., secondary cancers at distance from the primary tumor), often they also show multidrug resistance, which means that they hardly react to conventional chemotherapy. It is thought that the development of a normal cell to a metastatic cell is a continuous process driven by genetic damage and genomic instability, with the progressive selection of cells that have acquired a selective advantage within the particular tissue environment (Multistep Development). Studies of colorectal cancers have identified six to seven genetic events required for the conversion of a normal cell to a cell with metastatic ability. This is in contrast to leukemias, which usually require one genetic event, most often a translocation, for disease development.
Sporadic Versus Familial Cancer
The vast majority of cancers are “sporadic,” which simply means that they develop in an individual. Descendants of this individual do not have an increased risk because the cellular changes that have resulted in cancer development are confined to this individual. In contrast, ∼10–15% of cancer cases have a clearly recognizable hereditary background; they show familial clustering. Prominent examples include retinoblastoma (Retinoblastoma, cancer genetics), breast cancer, FAP (APC Gene in Familial Adenomatous Polyposis), and HNPCC as familial forms of colorectal cancer (Colon Cancer, Melanoma). This is not to say that “sporadic” cancers never are related to heredity. In fact, it is well possible that an undetermined fraction, if not all, “sporadic” cancers may be related to an individual inherited susceptibility that does not appear as a strong single gene determinant, but rather as a genetic constitution consisting of complex balance of polymorpic genes.
Familial cancers have been identified to result from germ line mutation of genes. These germ line mutations do not always directly dictate cancer development, although they are considered “strong” hereditary determinants. They represent susceptibility genes that confer a high risk for cancer development to the gene carrier. The relative risk of the individual carrying the mutant gene can vary considerably. For instance, the risk of carriers of one of the breast cancer susceptibility genes BRCA1 or BRCA2 for breast cancer development can vary between approximately 60% and 90%. In reality, this means that the risk for cancer development is difficult to predict, and individuals may not develop cancer at all in spite of the presence of a mutated gene in their germ line. The molecular basis for the differences in risk is unknown. Formally, the activity of modifying factors, either environmental or genetic, has been suggested. Such modifying factors appear to be less important for some other familial cancers, such as retinoblastoma, where the risk is constant between 90% and 95% for gene carriers.
Polygenic Determinants of Risk
The relative risk of the individual for cancer development can also be determined by so called “weak” genetic factors. Normal cells contain a number of genes involved in detoxification reactions. Different allelic variants of these genes exist in the human population that encode proteins with slightly different enzymatic activities. Although the exact contribution of individual allelic variants to cancer development is difficult to assess, it is reasonable to assume that individuals that have inherited “weak” enzymatic activities in different detoxification systems are likely to have a higher risk. It is likely, therefore, that the risk for such cancers is “polygenic.”