Research Early Theories About Cancer Causes.docx

Early Theories about Cancer Causes From the earliest times, physicians have puzzled over the causes of cancer. Ancient Egyptians blamed cancers on the gods.

Humoral theory Hippocrates believed that the body had 4 humors (body fluids): blood, phlegm, yellow bile, and black bile. When the humors were balanced, a person was healthy. The belief was that too much or too little of any of the humors caused disease. An excess of black bile in various body sites was thought to cause cancer. This theory of cancer was passed on by the Romans and was embraced by the influential doctor Galen’s medical teaching, which remained the unchallenged standard through the Middle Ages for over 1,300 years. During this period, the study of the body, including autopsies, was prohibited for religious reasons, which limited progress of medical knowledge.

Lymph theory Among theories that replaced the humoral theory of cancer was the formation of cancer by another body fluid, lymph. Life was believed to consist of continuous and appropriate movement of the fluid parts of the body through the solid parts. Of all the fluids, the most important were blood and lymph. Stahl and Hoffman theorized that cancer was composed of fermenting and degenerating lymph, varying in density, acidity, and alkalinity. The lymph theory gained rapid support. John Hunter, the Scottish surgeon from the 1700s, agreed that tumors grow from lymph constantly thrown out by the blood.

Blastema theory In 1838, German pathologist Johannes Muller demonstrated that cancer is made up of cells and not lymph, but he believed that cancer cells did not come from normal cells. Muller proposed that cancer cells developed from budding elements (blastema) between normal tissues. His student, Rudolph Virchow (1821-1902), the famous German pathologist, determined that all cells, including cancer cells, are derived from other cells.

Chronic irritation theory Virchow proposed that chronic irritation was the cause of cancer, but he believed incorrectly that cancers “spread like a liquid.” In the 1860s, German surgeon, Karl Thiersch, showed that cancers metastasize through the spread of malignant cells and not through some unidentified fluid.

Trauma theory Despite advances in the understanding of cancer, from the late 1800s until the 1920s, trauma was thought by some to cause cancer. This belief was maintained despite the failure of injury to cause cancer in experimental animals.

Infectious disease theory Zacutus Lusitani (1575-1642) and Nicholas Tulp (1593-1674), 2 doctors in Holland, concluded at almost the same time that cancer was contagious. They made this conclusion based on their experiences with breast cancer in members of the same household. Lusitani and Tulp publicized the contagion theory in 1649 and 1652, respectively. They proposed that cancer patients

should be isolated, preferably outside of cities and towns, in order to prevent the spread of cancer. Throughout the 17th and 18th centuries, some believed that cancer was contagious. In fact, the first cancer hospital in France was forced to move from the city in 1779 because people feared cancer would spread throughout the city. Although human cancer, itself, is not contagious, we now know that certain viruses, bacteria, and parasites can increase a person’s risk of developing cancer. symptoms and may require surgical removal. In rare cases, fibroids can change and eventually become cancerous. They are then called fibrosarcomas.

Hemangiomas A hemangioma on the scalp of a child

Hemangiomas are benign tumors that consist of excessive blood cells. They can sometimes be seen on the surface of the skin and are known as strawberry marks. The majority of hemangiomas appear at birth and gradually go away after some months or years. Hemangiomas do not usually require any treatment. If they affect the ability of an individual to eat, hear, or see, the doctor may recommend treatment with corticosteroids. If the patient is over 10 years of age, they are more commonly removed using laser surgery.

Lipomas Lipomas are the most common form of soft-tissue tumor.

They consist of fat cells. Most of them are very small, painless, soft to the touch, and generally movable. They are more common among people aged over 40 years. Experts disagree on whether lipomas can change and become cancerous. There is a range of lipomas, including: 

angiolipoma

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myelolipoma

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fibrolipoma

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spindle cell lipoma

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hibernoma

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atypical lipoma

Premalignant This type of tumor requires close monitoring Examples of premalignant growths include:

Actinic keratosis Also known as senile keratosis or solar keratosis, this is a premalignant growth consisting of patches of skin that turn crusty, scaly, and thick. Fair-skinned people are more at risk of developing these types of growths, especially those who are overexposed to sunlight. Actinic keratoses are seen as potentially premalignant, because around 20 percent of them progress to squamous cell carcinoma. Doctors usually recommend treating them because of this. Continuous exposure to the sun increases the risk of malignancy.

Cervical dysplasia This is a change in the normal cells lining the cervix. The growth can be premalignant and is at risk of developing into cervical cancer. Cervical dysplasia is diagnosed with a PAP smear. It is most common in women aged 25 to 35 years and may be removed with freezing techniques or by removing the cone of tissue from the cervix.

Metaplasia of the lung These growths occur in the tubes that carry air from the windpipe into the lung, or the bronchi. The bronchi are lined with glandular cells, which can change and become squamous cells. Metaplasia of the lung is most commonly caused by smoking.

Leukoplakia Thick, white patches can form on the gums, the bottom of the mouth, the insides of the cheeks, and, less commonly, on the tongue. They cannot be scraped off easily. Experts believe smoking or chewing tobacco is the main cause. Although Leukoplakia is rarely dangerous, a small percentage can eventually become cancerous. Many mouth cancers occur near areas of leukoplakia. The condition usually clears up when people quit smoking. Quitting both alcohol and tobacco together has better results. The patches can be removed using a laser, a scalpel, or a cold probe that freezes the cancer cells.

Malignant

Malignant tumors divide and spread rapidly, colonizing new areas.

Malignant tumors are cancerous tumors that can potentially result in death. Unlike benign tumors, malignant ones grow quickly, and can spread to new territory in a process known as metastasis. The abnormal cells that form a malignant tumor multiply at a faster rate. The cancer cells that metastasize are the same as the original ones. If a lung cancer spreads to the liver, the cancer cells now growing in the liver are still lung cancer cells. They have, however, acquired the ability to invade other organs. Different types of malignant tumor are made up of specific types of cancer cells, including: 

Carcinoma: These tumors are formed from epithelial cells. For example, carcinomas can occur in the stomach, prostate, pancreas, lung, liver, colon, or breast. Many of the most common tumors are carcinomas, especially among older adults.

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Sarcoma: These tumors start in connective tissue, such as cartilage, bones, fat, and nerves. They originate in the cells outside the bone marrow. The majority of sarcomas are malignant.

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Germ cell tumor: These are tumors made from the cells that give life, sperm and egg cells. Germ cell tumors most commonly occur in the ovaries or testicles. The majority of testicular tumors start from germ cells. Less commonly, germ cell tumors may also appear in the brain, abdomen or chest.

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Blastoma: Tumors formed from embryonic tissue or developing cells are known as blastomas and are more common in children than adults. Examples include medulloblastoma and glioblastoma, types of brain tumor, retinoblastoma, a tumor in the retina of the eye, osteoblastoma, a type of bone tumor, and neuroblastoma, a tumor of the nervous system found in children.

Diagnosis To diagnose a tumor and decide whether a tumor is malignant or not, a sample must be taken by a surgeon or an interventional radiologist, sent to a laboratory, and examined under a microscope by a pathologist. This sample is called a biopsy. There are three different types of biopsy: 

Excisional biopsy: This involves the surgical removal of the entire lump or suspicious area.

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Incisional or core biopsy: In this type of biopsy, a sample is surgically removed from the tumor.

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Needle aspiration biopsy: Fluid or a sample of tissue is removed with a needle. Samples are often taken from different parts of the tumor for the most accurate results.

Outlook The outlook of a tumor will depend entirely on its type. A benign tumor may pose no health problems at all. A malignant tumor, however, can be fatal and difficult to treat. The severity of a malignant tumor also depends on the location of the tumor and how quickly it can metastasize. If you find a lump on your body that you suspect could be a tumor, have it checked by a doctor. The earlier a tumor can be identified, the quicker it can be treated if required.

RELATED COVERAGE What is cancer? The word cancer is derived from the Latin word for crab because cancers are often very irregularly shaped, and because, like a crab, they "grab on

and don't let go." The term cancer specifically refers to a new growth which has the ability to invade surrounding tissues, metastasize (spread to other organs) and which may eventually lead to the patient's death if untreated. The terms tumor and cancer are sometimes used interchangeably which can be misleading. A tumor is not necessarily a cancer. The word tumor simply refers to a mass. For example, a collection of fluid would meet the definition of a tumor. A cancer is a particularly threatening type of tumor. It is helpful to keep these distinctions clear when discussing a possible cancer diagnosis. neoplasm- A neoplasm is an abnormal new growth of cells. The cells in a neoplasm usually grow more rapidly than normal cells and will continue to grow if not treated. As they grow, neoplasms can impinge upon and damage adjacent structures. The term neoplasm can refer to benign (usually curable) or malignant (cancerous) growths. tumor-

A tumor is a commonly used, but non-specific, term for a neoplasm. The word tumor simply refers to a mass. This is a general term that can refer to benign (generally harmless) or malignant (cancerous) growths.

benign

Benign tumors are non-malignant/non-cancerous tumor. A benign

tumor-

tumor is usually localized, and does not spread to other parts of the body. Most benign tumors respond well to treatment. However, if left untreated, some benign tumors can grow large and lead to serious disease because of their size. Benign tumors can also mimic malignant tumors, and so for this reason are sometimes treated.

malignant

Malignant tumors are cancerous growths. They are often resistant to

tumor-

treatment, may spread to other parts of the body and they sometimes recur after they were removed.

cancer-

A cancer is another word for a malignant tumor (a malignant neoplasm).

What is Pancreatic Cancer? Cancer of the pancreas is a malignant neoplasm that arises in the pancreas. It strikes approximately 9 out of every 100,000 people every year in the United States and is one of the deadliest forms of cancer. It is estimated that this year 45,000 Americans will be diagnosed with cancer of the pancreas. An almost equal number of patients (some diagnosed previous to this year) will die from pancreatic cancer during this year. Cancer of the pancreas is not one disease. In fact, as many as twenty different tumors have been lumped under the umbrella term "cancer of the pancreas." Each of these tumors has a different appearance when examined with a microscope, some require different treatments, and each carries its own unique prognosis (predicted or likely outcome). An understanding of the different types of neoplasms of the pancreas is required for rational treatment.different types of pancreatic tumors is required for rational treatment. Cancers of the pancreas can be broadly classified as: Primary-

Primary cancers are those that arise in the pancreas itself.

Metastatic- tMetastatic cancers are cancers that arise in other organs and only later spread to the pancreas. These are usually not considered a pancreatic cancer, instead they are considered cancers of the organs

from which they arose.

In the vast majority of cases the term "cancer of the pancreas" refers to primary cancers of the pancreas — cancers that arose in the pancreas. Primary cancers of the pancreas can be broadly subgrouped into those that look like endocrine cells under the microscope (have endocrine differentiation) and those that look like exocrine cells under the microscope (have exocrine differentiation). The distinction between endocrine neoplasms and exocrine neoplasms is very important and will greatly impact on treatment and outcome. Pathologists examine histological slides (slides of tissue samples) using a microscope to diagnose and classify pancreatic cancer. To make the cells visible the slides are stained with various dyes. A change in color from one slide to another does not indicate any disease or abnormality. The different colors indicate that a different dye has been used or a different part of the cells is stained. Pathologists identify abnormalities by changes in the size, shape or arrangement of cells. The classification of neoplasms of the pancreas given below is based on pathological examination. A neoplasm is a type of abnormal and excessive growth, called neoplasia, of tissue. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and it persists growing abnormally, even if the original trigger is removed.[1][2][3] This abnormal growth usually (but not always) forms a mass.[4] When it forms a mass, it may be called a tumor. ICD-10 classifies neoplasms into four main groups: benign neoplasms, in situ neoplasms, malignant neoplasms, and neoplasms of uncertain or unknown behavior.[5] Malignant neoplasms are also simply known as cancers and are the focus of oncology. Prior to the abnormal growth of tissue, as neoplasia, cells often undergo an abnormal pattern of growth, such as metaplasia or dysplasia.[6] However, metaplasia or dysplasia does not always progress to neoplasia.[1] The word is from Ancient Greek νέος- neo ("new") and πλάσμα plasma ("formation", "creation"). A neoplasm can be benign, potentially malignant, or malignant (cancer).[7]

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Benign tumors include uterine fibroids, osteophytes and melanocytic nevi (skin moles). They are circumscribed and localized and do not transform into cancer.[6] Potentially-malignant neoplasms include carcinoma in situ. They are localised, do not invade and destroy but in time, may transform into a cancer. Malignant neoplasms are commonly called cancer. They invade and destroy the surrounding tissue, may form metastases and, if untreated or unresponsive to treatment, will prove fatal. Secondary neoplasm refers to any of a class of cancerous tumor that is either a metastatic offshoot of a primary tumor, or an apparently unrelated tumor that increases in frequency following certain cancer treatments such as chemotherapy or radiotherapy. Rarely there can be a metastatic neoplasm with no known site of the primary cancer and this is classed as a cancer of unknown primary origin 

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DNA damage is considered to be the primary underlying cause of malignant neoplasms known as cancers.[15][16] Its central role in progression to cancer is illustrated in the figure in this section, in the box near the top. (The central features of DNA damage, epigeneticalterations and deficient DNA repair in progression to cancer are shown in red.) DNA damage is very common. Naturally occurring DNA damages (mostly due to cellular metabolism and the properties of DNA in water at body temperatures) occur at a rate of more than 60,000 new damages, on average, per human cell, per day[15] [also see article DNA damage (naturally occurring) ]. Additional DNA damages can arise from exposure to exogenous agents. Tobacco smoke causes increased exogenous DNA damage, and these DNA damages are the likely cause of lung cancer due to smoking.[17] UV light from solar radiation causes DNA damage that is important in melanoma.[18]Helicobacter pylori infection produces high levels of reactive oxygen species that damage DNA and contributes to gastric cancer.[19] Bile acids, at high levels in the colons of humans eating a high fat diet, also cause DNA damage and contribute to colon cancer.[20] Katsurano et al. indicated that macrophages and neutrophils in an inflamed colonic epithelium are the source of reactive oxygen species causing the DNA damages that initiate colonic tumorigenesis.[21] Some sources of DNA damage are indicated in the boxes at the top of the figure in this section. Individuals with a germ line mutation causing deficiency in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) are at increased risk of cancer. Some germ line mutations in DNA repair genes cause up to 100% lifetime chance of cancer (e.g., p53mutations).[22] These germ line mutations are indicated in a box at the left of the figure with an arrow indicating their contribution to DNA repair deficiency. About 70% of malignant neoplasms have no hereditary component and are called "sporadic cancers".[23] Only a minority of sporadic cancers have a deficiency in DNA repair due to mutation in a DNA repair gene. However, a majority of sporadic cancers have deficiency in DNA repair due to epigenetic alterations that reduce or silence DNA repair gene expression. For example, of 113 sequential colorectal cancers, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[24] Five reports present evidence that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.[25][26][27][28][29] Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[30] In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[31] In further examples, epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM. These epigenetic defects

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occurred in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.[32] Epigenetic alterations causing reduced expression of DNA repair genes is shown in a central box at the third level from the top of the figure in this section, and the consequent DNA repair deficiency is shown at the fourth level. When expression of DNA repair genes is reduced, DNA damages accumulate in cells at a higher than normal level, and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates strongly increase in cells defective in DNA mismatch repair[33][34] or in homologous recombinational repair (HRR).[35] During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[36][37] DNA repair deficiencies (level 4 in the figure) cause increased DNA damages (level 5 in the figure) which result in increased somatic mutations and epigenetic alterations (level 6 in the figure). Field defects, normal appearing tissue with multiple alterations (and discussed in the section below), are common precursors to development of the disordered and improperly proliferating clone of tissue in a malignant neoplasm. Such field defects (second level from bottom of figure) may have multiple mutations and epigenetic alterations. Once a cancer is formed, it usually has genome instability. This instability is likely due to reduced DNA repair or excessive DNA damage. Because of such instability, the cancer continues to evolve and to produce sub clones. For example, a renal cancer, sampled in 9 areas, had 40 ubiquitous mutations, demonstrating tumour heterogeneity (i.e. present in all areas of the cancer), 59 mutations shared by some (but not all areas), and 29 “private” mutations only present in one of the areas of the cancer. Various other terms have been used to describe this phenomenon, including "field effect", "field cancerization", and "field carcinogenesis". The term "field cancerization" was first used in 1953 to describe an area or "field" of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer.[39] Since then, the terms "field cancerization" and "field defect" have been used to describe pre-malignant tissue in which new cancers are likely to arise. Field defects are important in progression to cancer.[40][41] However, in most cancer research, as pointed out by Rubin[42] “The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion.[43] Similarly, Vogelstein et al.[44] point out that more than half of somatic mutations identified in tumors occurred in a preneoplastic phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects. An expanded view of field effect has been termed "etiologic field effect", which encompasses not only molecular and pathologic changes in pre-neoplastic cells but also influences of exogenous environmental factors and molecular changes in the local microenvironment on neoplastic evolution from tumor initiation to patient death.[45] In the colon, a field defect probably arises by natural selection of a mutant or epigenetically altered cell among the stem cells at the base of one of the intestinal crypts on the inside surface of the colon. A mutant or epigenetically altered stem cell may replace the other nearby stem cells by natural selection. Thus, a patch of abnormal tissue may arise. The figure in this section includes a photo of a freshly resected and lengthwise-opened segment of the colon showing a colon cancer and four polyps. Below the photo there is a schematic diagram of how a large patch of mutant or epigenetically altered cells may have formed, shown by the large area in yellow in the diagram. Within this first large patch in the diagram (a large clone of cells), a second such mutation or epigenetic alteration may occur so that a given stem cell acquires an advantage compared to other stem cells within the patch, and this altered stem cell may expand clonally forming a secondary patch, or sub-clone, within

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the original patch. This is indicated in the diagram by four smaller patches of different colors within the large yellow original area. Within these new patches (sub-clones), the process may be repeated multiple times, indicated by the still smaller patches within the four secondary patches (with still different colors in the diagram) which clonally expand, until stem cells arise that generate either small polyps or else a malignant neoplasm (cancer). In the photo, an apparent field defect in this segment of a colon has generated four polyps (labeled with the size of the polyps, 6mm, 5mm, and two of 3mm, and a cancer about 3 cm across in its longest dimension). These neoplasms are also indicated, in the diagram below the photo, by 4 small tan circles (polyps) and a larger red area (cancer). The cancer in the photo occurred in the cecal area of the colon, where the colon joins the small intestine (labeled) and where the appendix occurs (labeled). The fat in the photo is external to the outer wall of the colon. In the segment of colon shown here, the colon was cut open lengthwise to expose the inner surface of the colon and to display the cancer and polyps occurring within the inner epithelial lining of the colon. If the general process by which sporadic colon cancers arise is the formation of a preneoplastic clone that spreads by natural selection, followed by formation of internal subclones within the initial clone, and sub-sub-clones inside those, then colon cancers generally should be associated with, and be preceded by, fields of increasing abnormality reflecting the succession of premalignant events. The most extensive region of abnormality (the outermost yellow irregular area in the diagram) would reflect the earliest event in formation of a malignant neoplasm. In experimental evaluation of specific DNA repair deficiencies in cancers, many specific DNA repair deficiencies were also shown to occur in the field defects surrounding those cancers. The Table, below, gives examples for which the DNA repair deficiency in a cancer was shown to be caused by an epigenetic alteration, and the somewhat lower frequencies with which the same epigenetically caused DNA repair deficiency was found in the surrounding field defect.