What is Cancer?
Incidence of Cancer
Risk of cancer increases with age, and cancer results in 13% of all deaths (7.6 million deaths worldwide in 2007).What Causes Cancer?
Essentially, cancer is caused by cells that malfunction due to abnormalities in genetic material. Factors that cause abnormalities include:- Tobacco smoke
- Radiation
- Chemicals
- Infectious agents
Malignant and Benign Tumors
There is connection between the microscopic features of tumors and the effects of a tumor on the patient. Benign tumors grow without invading adjacent tissue, while malignant tumors invade nearby tissue and create metasteses.Biological Properties of Malignant Tumor Cells
Hanahan and Weinberg summarized in 2000 the biological properties of malignant tumor cells:[3] [2]
- Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
- Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
- Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
- Loss of capacity for senescence, leading to limitless replicative potential (immortality)
- Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
- Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
- Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).
- Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes.
How is Cancer Diagnosed?
Radiographic imaging abnormalities and histologic examination of a tissue biopsy specimen can indicate malignancy. Blood tests, x-rays, CT scans, and endoscopy are common methods of investigating cases of suspected cancer.Can Cancer Be Cured?
Cancer has been treated and cured with combinations of surgery, chemotherapy, and radiotherapy. Research results in ways to treat diseases more specifically, such as by targeted therapy drugs.History of Cancer Treatment
Surgery in Egypt
In Egypt there was the oldest description and surgical treatment of cancer, which involved cauterization with a "fire drill." Descriptions of eight types of breast ulcers were included in the Edwin Smith Papyrus, which said about this disease that, "there is no treatment."[1]500 BC - 0 AD
Hippocrates
Hippocrates, an ancient Greek physician, designated between two types of cancer, benign and malignant. Treatment was based on the humour theory (the four bodily fluids were believed to be black and yellow bile, blood, and phlegm). Blood-letting, diet, and laxatives were means to treat the disease, and humour-based therapy was popular until the 19th century.Galen
Galen was a Roman physician who believed in the humoral theory of medicine. He though that cancer was curable when treated in the early stages and that cutting or cauterizing advanced tumors was appropriate.0 AD - 1500 AD
Paul of Aegina (~625 - 690 AD)
Paul of Aegina was a most prominent Byzantine physician who believed cancer of the breast and uterus were most common, and he wrote that surgery of uterine cancer was useless. He recommended removal of breast cancer instead of cauterizaion.[9]Moses Maimonides (1135 - 1204 AD)
The treatment of large tumors suggested by Moses Maimonides involves "excis[ing] the tumor and uproots the entire tumor and its surroundings up to the point of healthy tissue, except if the tumor contains large vessels...[or] the tumor happens to be situated in close proximity to any major organ, excision is dangerous." [8]Renaissance Period
Bernardino Ramazzini in 1715 observed a virutally nil incidence of cervical cancer in nuns but an increased rate of breast cancer. This was correlated with lifestyle factors, particularly abstinence, and led to future discoveries of the connectinos between hormonal factors and the disease of cancer.
Percival Pott showed in 1775 that the soot collected under the scrotum of chimney sweeps increased the risk of cancer. This led to studies that identified additional carcogenic hazards that public health measures were initiated in response.
Nineteenth Century
During the 19th century, the use of the modern microscope began. Rudolf Virchow provided the scientific basis the modern study of cancer. Morgagni connected the microscopic pathology of cancer with autopsy findings. Body tissue was surgically removed and be examined to make precise diagnosis. Also, a pathologist could communicate to a surgeon whether a tumor was completely removed.
Major advances in surgery occurred in the 19th and 20th centuries, a time associated with "the century of the surgeon." The work of Bilroth, Handley, and Halsted led to "cancer operations" aiming to remove the tumor and the neighboring lymph nodes. Halsted based his work in part on that of Sampson Handley, who was a London surgeon who postulated that cancer spread by invasion from the original growth. During the 1870s and 1880s, there several first successful operations to remove organs to treat cancer:
- Freund was the first in 1878 to successfully remove the uterus in order to treat uterine cancer. [12]
- Billroth performed the first pyloric resection (surgical removal of part or all of the stomach) to treat carcinoma. [13]
- Billroth first performed an esophageal resectinon in 1872 to treat carcinoma. [13]
- Halsted in 1890 performed the radical mastectomy, involving removing the breast, the muscles in front of the chest, and the lymphatic system of the breast, to treat breast cancer
Muller in 1838 published a paper "On the Nature and Structural Characteristics of Cancer, and of Those Morbid Growths Which May Be Associated with It", and this helped establish pathological histology as an independent branch of science. Muller showed that cancer consists of cells, and he thought cancer cells came from abnormal cells. [11] Virchow (1863-1867) was a student of Muller and theorized that cancer spread analogolously to a liquid
Stephen Paget was an English surgeon who believed cancer cells spread via the bloodstream. He compared cancer mestasis to seeds that "are carried in all directions, but they can only live and grow if they fall on congenial soil." [1] Paget studied 735 cases of case histories of fatal breast cancer and found that metastases formed in the liver in many more cases than other organs. [7] The "seed and soil hypothesis" of 1889 was confirmed a hundred years later by modern cellular and molecular biology.
Thomas Beatson in 1878 discovered that rabbits stopped producing milk after removal of ovaries. "This fact seemed to me of great interest, for it pointed to one organ holding control over the secretion of another and separate organ." Beatson found that ophorectomy, the removal of ovaries, improved the condition of breast cancer patients. This work was foundational to the modern use of hormone therapy.
In 1890, David von Hansemann postulated that aberrant cell divisions result in abnormal amounts of chromatin in cancer cells. [7] The research of David von Hansemann contributed to the understanding of cancer as a disease genetic in origin.
Rontgen discovered x-rays in 1895, which facilitated the detection of tumors, and Sjogren first successfully treated cancer with x-rays in 1899.
Twentieth Century
Topics of biological revelation of the twentieth century include genetics and heredity, the growth and division of cells, the assembly of cells to form tissue, and the genetic control of tissue. Revolutions have altered how cancer is treated.Theodor Boveri, a zoologist, at the start of the twentieth century made numerous accurate and bold predictions:
- The existence of cell-cycle checkpoints, tumour-supressor genes, and oncogenes
- The role of 'poisons', radiation, physical insults, pathogens, chronic inflammation, and tissue repair in contributing to aberrant mitoses and additional events that cause chromosome imbalances.
- The emergence of different types of tumor types in a tissue
- The clonal origin of tumours
- The heritability of cancer susceptibilities
- The sensitivity of cancer cells to radiotherapy
1909 - Immune Surveillance
The immune system can generally differentiate between cells that are from a particular individual and foreign cells. Since tumor cells are characterized by mutations and different gene expression, using the immue system to destroy cancer cells may be possible. Paul Ehrlich in 1909 postulted that tumor development is usually suppressed due to the immune system.
Aline van Pel and Thierry Boon in 1982 discovered that specific immunity to tumors could be generated with vaccination of mutagenized tumor cells in mice. This showed that spontaneous tumors did not lack tumor antigens but that they did not stimulate an effective immune response. Vaccination has been a goal of many clinical trials.
The Boon group also reported an identification of a tumour-specific antigen that is recognized by cytolytic T cells. In 2001, Robert Schreiber showed that immunodeficient mice are more likely to form chemically-induced and spontaneous tumors. [7]
The Boon group also reported an identification of a tumour-specific antigen that is recognized by cytolytic T cells. In 2001, Robert Schreiber showed that immunodeficient mice are more likely to form chemically-induced and spontaneous tumors. [7]
1910 - Viruses and Cancer
Reyton Rous discovered in 1910 the first avian tumor, which originated in a hen, that could be transpanted to others. Rous would inoculate part of the tumor into the breast and peritoneal of hens to transfer and propogate the tumor. A year later he used cell-free filtrates of the tumor to induce tumor growth, and the agent in this filtrate was shown to be a virus, the Rous sarcoma virus (RSV). [7]
Robert Huebner and George Todaro proposed on the basis of experimental evidence that there is a class of viruses that plays an important role in the development of tumours in animals. They believed that the C-type retrovirus could be transmitted from animal to progeny animal and that the activation results in oncogene expression and cell transformation. Their work led to identifying the first retroviral oncogenes. [7]
1915 - Hormones and Cancer
Hormones have been shown to influence the initiation and progression of cancer, and the study of the relationship between oestrogen and breast cancer has resulted in important revelations. In 1915, Abbie Lathrop and Leo Loeb were the first to report about the influence of secretions of the ovarian follicles on the development of tumors in mice. Female mice castrated before reaching six months age were associated with a delayed and reduced tumor incidence from 60 - 90 % to 9 %. Lathrop and Loen suggested that the chemical secreted from the ovarian follicles was involved in tumor formation. After eight years, Edgar Allen and Edward Doisy determined this chemical is oestrogen. [7]
The research of Elwood Jenseen in 1958 and 1971 involving the discovery of the oestrogen receptor (ER) and the effect of adrenalectomy on human breast cancer resulted in a revolution. From the facts that breast tumour cells could be categorized as either ER-rich or ER-poor and that this correlated with the level of response to hormone-ablative therapy, Jensen proposed that the level of ER was a predictative measure of the response to therapy. The drug tamoxifen was developed in the 1970s as an anti-oestrogenic cancer drug, and it results in a 50% reduction in the incidence of breast cancer. [7]
1937 - Cancer Stem Cells
Understanding about cancer stem cells (CSCs) has resulted from studyies of haematopoietic malignancies. Jacob Furth and Morton Kahn talked about CSC principles in 1937. They showed that a single leukaemic cell transmitted leukemia when it was transplanted into mice. In the 1960s and 1970s, quantitative methods were developed to measure the clonogenic potential to sustain tumor growth. The spleen colony-forming assay was used by Robert Bruce and Hugo Van der Gaag to show that only a small subset of primary cancer tissue could proliferate in the body. Definitive proof of the stem cell model of cancer was provided by the identification and purification of CSCs in 1994. John Dick and colleagues showed that only a fraction of tumor cells with a characteristic marker established leukemia in recipient mice. These cells that initiate acute myeloid leukaemia (AML) differentiated, proliferated, and importantly could self-renew in vivo - all characteristics of stem cells. This model of the formation of tumors has been shown to extend to solid tumors, including human breast and brain tumors, which has motivated research to learn about mechanisms that regulate CSC function. [7]
1939 - Angiogenesis
Gordon Ide and colleagues studied the growth of blood vessels near tumor tissue that had been transplanted in rabbit ear. They suggested that tumors create a 'vessel growth-stimulating substance'. Glenn Algire and colleagues researched further by means of a detailed kinetic analysis of vascular response of tumor transpants. They thought that the growth advantage of tumor cells was due to the formation of blood vessels. Inhibiting angiogenesis has been exploited as a therapeutic strategy. [7]
Melvin Greenblatt and Philippe Shubik have shown that tumor transplants cause the proliferation of blood vessels even when there is a physical barrier between the tumor and host stroma. Abut three years later, in 1971, Judah Folkman and colleagues isolated "tumor angiogenic factor (TAF)" from tumor extracts. They thought that the growth of malignancies could be prevented if activity of TAF were blocked. Vascular endothelil growth factor (VEGF) is a secreted protein that can stimulate vascular endothelial cell proliferation in vitro and angiogensis in vivo. By inhibiting the function of VEGF using an antibody, scientists showed that VEGF stimulates tumor angiogenesis and growth in mice. This has led to the development and clinical application of Avastin, which is a humanized version of the antibody. This drug was approved by the United States Food and Drug Administration in 2004 to treat metastatic colorectal cancer. [7]
1950 - Smoking and Cancer
The research of Tony Hill and Richard Doll has contributed greatly to the accepted view that most types of lung cancer is caused by cigarette smoking. A 1939 German study indicated that non-smokers were more often healthy than suffering from lung cancer. In about 1950, there was reported in the British Medical Journal a case-control study that concluded that smoking is an important cause of cancer. [7]
1953 - Two-Hit Hypothesis
Alfred Knudson in 1971 analyzed about fifty cases of retinoblastoma to determine the occurrence of bilateral or unilateral tumours and the family history of the disease. Poisson statistics were used to show that the distribution supported the initiation of the disease by two mutations. One mutation could be inherited, while the other would be acquired later, or two mutations would be somatic in sporadic tumors. The hypothesis that two mutations could cause cancer merged with the concept of allelic loss of tumor-suppresor genes. [7]
1960 - Chromosome Translocations
The first genetic defect that was associated with cancer is a small chromosome, the Philadelphia chrmosome, in cancer cells from patients of chronic myelogenous leukemia (CML). In the chromosome is the transforming sequence of Abelson murine leukemia virusm which is associated with the generation of human leukemia. The presence of the chromosome is a product of translocation, and this knowledge has led to discovery of additional chromosomal translocations and oncogenes of different types of cancer, including B-cell lymphoma 2 and tumor suppressor genes. [7]
1971 - Tumour Suppressor Genes
David Comings in 1971 proposed a framework of the role of tumor supressor genes in causing all kinds of cancer. He thought that inherited tumors result from a germline mutation in regulatory genes that suppress tumorigenesis and a somatic loss of a homologous allele. Both alleles are affected in somatic cells in non-heritable cancers. [7]
A decade later, Webster Cavanee and colleagues showed that sporadic cancers were associated with the same mutations in a small region of chromosome 13, where the retinoblastoma gene is. Near this time, the first two tumour suppressor genes were identified - RB and p53. [7]
1972 - Apoptosis and Cancer
Many experiments have shown that failure to induce apoptosis results in hyperplasia but that more mutations are necessary to result in neoplasia. Treatment strategies have been influenced by this idea, which was first proposed in 1972 by John Kerr, Andrew Wyllie, and Alastair Currie: "We should now like to speculate that hyperplasia might sometimes result from decreased apoptosis rather than increased mitosis, although we emphasize that we know of no definitive studies to support suh a hypothesis." [7]
1975 - Tumor Microenvironment
Research in the 1970s demonstrated that tumors must be in an environment that is conducive to growth in ways beyond an appropriate blood supply. In 1975, Beatrice Mintz and Karl Illmensee tested what happens when mouse tetracarcinoma cells are placed in the environment of developing mouse blastocysts. In this case, normal mice were born without immediate indication of tumors. Upon closer investigation, the authors found that there was actually a large number of tumor-derived cells. In 1984, Mina Bissel and David Dolberg found that Rous sarcoma virus is able to induce tumors only when in the correct environment. During the previous decade, scientists have grown in understanding the molecular basis of how the local tissue environment influences tumorigenic cells. [7]
1976 - Clonal Evolution and Multistep Tumorigenesis
Leslie Foulds was one of the first to describe the formation of cancer as a dynamic process, which progresses from precancerous stages to more invasive and metastatic stages. Peter Nowell in 1976 wrote about how cancer could be caused by may mutations or 'hits'. He postulated that a first step is creation of cells that are able to proliferate in an unrestrained manner. Further clonal selection results in more aggressive phenotypes. Nowell wrote about how DNA-repair defects, mitotic errors, and diverse agents can result in genetic changes. The accumulation of mutations in oncogenes and tumor-suppressor genes and the stepwise selection of increasingly malignant tumor-cell populations has been incorporated in a model of cancer evolution. The foresight of Nowell is praiseworthy in that he suggested that differences in genetic and biological changes in tumors might necessitate personalized therapies. [7]
1976 - Cellular Homologues of Viral Oncogenes
In 1976, Michael Bishop, Harold Varmus, and Dominique Stehelin found that RSV was able to transform cells by recombining with and transducing the chicken celllular 'c-src' oncogene. Studies showed, as Bishop stated, that "the seeds of cancer are within us". Forty different oncogenes were later identified after much research into oncogenes, and this helped created a framework of understanding signal-transduction pathways. [7]
1978 - Oncogenes Encode Proteins that Regulate Cell Growth
After the discovery of oncongenes, research was initiated in an effort to discover what protein products the oncogenes encode. In 1978, a protein was found that likely functions as a kinase in the transformation process associated with the avian Rous sarcoma virus (RSV). The study indicated that protein phosphorylation was likely necessary in the process of transformation. Papers in 1983 and 1984 indicated that oncogenes associated with retroviruses encode components of the normal growth-regulatory machinery of the cell. These studies motivates the development of therapeutic agents that target mutated oncogenes. [7]
1979 - First Human Oncogene
Proof that cancer is a disease of altered genes was established in the late 1970s when it was found that mutations in the genome of tumor cells when tranferred to other cells cause transformation. After rounds of cloning, in 1982, an actual oncogene was cloned using linked sequence tags. The cloned cellular genes were able to transform in a way similar to oncogenes from retroviruses. Three different groups each discovered the same single amino-acid change that distinguished the normal cellular human c-Ha-RAS1 gene from a transforming counterpart. These developments led to the understanding of cancer as an interplay between various genetic lesions. [7]
1983 - Oncogene Co-Operation
Scientists in the early 1980s believed that oncogenic transformation of primary cells was associated with two stages: establishment and cellular transformation. Hartmut Land, Luis F. Parada, and Robert Weinberg investigated how oncogenes interact in the development of tumors. With molecular techniques, it's possible to learn how oncogenes cooperate effectively, and learn about the pathways that have evolved to limit cellular transformation. [7]
Two proteins, RAS and MYC, cooperate in the formation of tumors. High expression levels of RAS induce G1 arrest in primary cells due to the expression of a cell-cycle inhibitor p21, and expression of MYC induces proliferation and apoptosis. B-cell lymphoma 2 (BCL ) and MYC also cooperate. Expression of BCL2 results in suppression of MYC-induced apoptosis, which results in the proliferative capacity of MYC being unchecked. [7]
1983 - Cancer Epigenetics
Epigenetics involves changes in cellular information other than DNA sequence that is heritable. Research in the 1980s demonstrated that epigenetic changes can occur in oncogenes and tumor suppressors. This has led to a further understanding of epigenetic markers as cancer diagnostics and therapeutic targets. [7]
1989 - Cell and DNA Damage Checkpoints
A crucial guardian of the genome is p53, and it is known that p53 and DNA damage inhibit DNA replication and cause G1 cell-cycle arrest. Studies in the 1980s have helped understand the role of RB and p53 and their role in cell-cycle and DNA-damage checkpoints. This has dominated cancer research during the past decade. [7]
1990 - Genetic Basis of Cancer Predisposition
During the late 1980s and early 1990s, numerous tumour-suppressor genes were discovered that are inherited in mutant form, and these genes are associated with cell proliferation, cell-cycle checkpoints and cell death. Being able to identify these genes through testing has enabled informed prophylactic-care decisions. [7]
1990 - Mechanisms of Genetic Instability in Cancer
Many cancers are caused by mutations in oncogenes and tumor-supressor genes, and cancer can also be caused indirectly by the protective cellular mechanisms that repair DNA damage. This idea was first stated by Theodor Boveri in a study of chomosomal imbalances in somatic cells. The DNA damage that causes cancer ranges from single unrepaired base lesionss to macroscopic lesions. Genetic instabilities predispose cancer by increasing rates at which possible oncogenic mutations and chromosomal alterations happen. [7]
1999 - Cancer Profiling
Cancers with similar morphologies and histopathological features can respond to therapy in very different ways. Microarray technology enables classifying cancers in ways that help to better predict clinical outcomes. Tom Golub, Donna Slonim and colleagues in 1999 were able to distinguish between two types of leukaemia and predict the responsiveness to therapy based on expression-profile differences. Gene-expression data has also been used to determine metastatic potential. [7]
2001 - Targeted Cancer Therapy
Discovering oncogenes has enabled creation of drugs that target genetic abnormalities that allow cells to grow uncontrollably. One such drug is Trastuzumab, which blocks human epidermal growth factor receptor 2 (HER2) protein, which is overexpressed in 25% of breast cancer cases. [7]
Modern Cancer Treatments
Understanding metastasis has allowed doctors to use systemic treatments after surgery to eliminate cells that spread through the body. Less mutilating operations are often used; the radical masectomy is very rarely performed. A lumpectomy, or local removal of the primary tumor, is combined with radiation therapy and chemotherapy.Radiation therapy is one of several less invasive surgical techniques:
- Cryosurgery: treat prostrate cancer by freezing cells with a metal probe
- Radiation Therapy: Radiation therapy utilizes ionizing radiation to kill cancer cells and decrease the size of tumors. Radiation therapy is used in the treatment of half of all cancer patients, and different kinds of radiation are used in treating different cancer types. Planning and simulation helps the treatment to be more precise, effective and less damaging to healthy tissue. [4]
- Hormone Therapy:
- Molecular-Targeted Drugs: Drugs can be used to block the growth and spread of cancer. These drugs interfere with molecules involved with carcinogenesis.
- Photodynamic Therapy of Cancer: A drug and type of light can be combined to kill cancer cells. When photosensitizers interact with light, a form of oxygen is produced that helps kill cancer cells. [6]
- Biological Therapy: The immune system can help fight cancer or control side effects. Biological therapy helps to slow the growth of cancer cells, destroy cancer cells, and stop spreading of cancer to other parts of the body. [5]
Knowledge from Modern Biology Impacts Cancer Treatment
Angiogenesis
New blood vessels form to facilitate growth and wound healing. A tumor must develop a supply of blood in order to grow, and drugs have been developed that prevent the formation of new blood vessels.Signal Transduction
Signal transduction involves the process in which growth signals are transmitted to the nucleus of a cell. There have been efforts to interfere with signaling.Genetic Therapy
There are genetic characteristics that we are able to target to treat cancer. Gene therapy involves the insertion of genes into cells and tissues in order to treat disease.Experimental Cancer Treatments
Bacterial Treatments
Anaerobic bacteria may be able to consume oxygen-poor tumours. The bacteria would die in the oxygenated sides of the tumor, and so they will likely not harm the healthy body. Combining this approach with chemotherapeutic treatments could help to eliminate all the cells.
Bactiera may also be able to trasform a nontoxic molecule to a toxic drug. If there is proliferation of bacteria in the necrotic and hypoxic areas of the tumor, then a systematically applied prodrug is converted to a toxic drug solely in the tumor.
Bactiera may also be able to trasform a nontoxic molecule to a toxic drug. If there is proliferation of bacteria in the necrotic and hypoxic areas of the tumor, then a systematically applied prodrug is converted to a toxic drug solely in the tumor.
Preventive Treatment
Hormone Treatment
In the early twentieth century, a urologist at the University of Chicago, Charles Huggins, discovered a regression of metastatic prostrate cancer after removal of testes. Drugs that block male hormone can effectively treat prostrate cancer and may play a role in prevention of prostrate cancer
References
- "The History of Cancer" American Cancer Society. Website of Cancer Reference Information
(link to site) - "Cancer" Wikipedia
(link to site) - Hanahan D, Weinberg RA (2000). "The hallmarks of cancer". Cell 100 (1): 57–70.
- "Radiation Therapy for Cancer: Questions and Answers" National Cancer Insitute
(link to site) - "Biological Therapy". National Cancer Institute
(link to article) - "Photodynamic Therapy for Cancer: Questions and Answers". National Cancer Institute
(link to article) - Nature Milestones Cancer
(link to article) - Timeline of Cancer - Moses Maimonides. cancerquest.org accessed August 3, 2008
(link to article) - Timeline of Cancer - Paul of Aegina . cancerquest.org accessed Augest 3, 2008
(link to article) - Timeline of Cancer - Recaimer. cancerquest.org accessed August 3, 2008
(link to site) - Timeline of Cancer - Muller. cancerquest.org accessed August 3, 2008
(link to site) - Treatment of Cancer - Freund. cancerquest.org accessed August 3, 2008
(link to site) - Treatment of Cancer - Billroth. cancerquest.org accessed August 3, 2008
(link to site) - Treatment of Cancer - Rontgen. cancerquest.org accesed August 3, 2008
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