Anatomy & Physiology Overview of the Gastrointestinal System Functions 1. Ingestion.

This process involves taking foods and liquids into the mouth (eating). 2. Secretion. Each day, cells within the walls of the GI tract and accessory digestive organs secrete a total of about 7 liters of water, acid, buffers, and enzymes into the lumen (interior space) of the tract. 3. Mixing and propulsion. Alternating contractions and relaxations of smooth muscle in the walls of the GI tract mix food and secretions and propel them toward the anus. This capability of the GI tract to mix and move material along its length is called motility. 4. Digestion. Mechanical and chemical processes break down ingested food into small molecules. In mechanical digestion the teeth cut and grind food before it is swallowed, and then smooth muscles of the stomach and small intestine churn the food. As a result, food molecules become dissolved and thoroughly mixed with digestive enzymes. In chemical digestion the large carbohydrate, lipid, protein, and nucleic acid molecules in food are split into smaller molecules by hydrolysis. Digestive enzymes produced by the salivary glands, tongue, stomach, pancreas, and small intestine catalyze these catabolic reactions. A few substances in food can be absorbed without chemical digestion. These include vitamins, ions, cholesterol, and water. 5. Absorption. The entrance of ingested and secreted fluids, ions, and the products of digestion into the epithelial cells lining the lumen of the GI tract is called absorption. The absorbed substances pass into blood or lymph and circulate to cells throughout the body. 6. Defecation. Wastes, indigestible substances, bacteria, cells sloughed from the lining of the GI tract, and digested materials that were not absorbed in their journey through the digestive tract leave the body through the anus in a process called defecation. The eliminated material is termed feces. Parts: 1. Mouth - The first portion of the alimentary canal that receives food and saliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth. - A salivary gland is a gland that releases a secretion called saliva into the oral cavity. Ordinarily, just enough saliva is secreted to keep the mucous membranes of the mouth and pharynx moist and to cleanse the mouth and teeth. When food enters the mouth, however, secretion of saliva increases, and it lubricates, dis- solves, and begins the chemical breakdown of the food. - The teeth, or dentes are accessory digestive organs located in sockets of the alveolar processes of the mandible and maxillae. - The tongue is an accessory digestive organ composed of skeletal muscle covered with mucous membrane. The extrinsic muscles move the tongue from side to side and in and out to maneuver food for chewing, shape the food into a rounded mass, and force the food to the back of the mouth for swallowing. 2. Pharynx - When food is first swallowed, it passes from the mouth into the pharynx a funnel-shaped tube that extends from the internal nares to the esophagus posteriorly and to the larynx anteriorly. The pharynx is composed of skeletal muscle and lined by mucous membrane, and is divided into three parts: the nasopharynx, the oropharynx, and the laryngopharynx. The nasopharynx functions only in respiration, but both the oropharynx and laryngopharynx have digestive as well as respiratory functions. Swallowed food passes from the mouth into the oropharynx and laryngopharynx; the muscular contractions of these areas help propel food into the esophagus and then into the stomach. 3. Esophagus - A collapsible muscular tube, about 25 cm (10 in.) long, that lies posterior to the trachea. The esophagus begins at the inferior end of the laryngopharynx and passes through the mediastinum anterior to the vertebral column. Then it pierces the diaphragm through an opening called the esophageal hiatus, and ends in the superior portion of the stomach. Histology - Keratinized stratified squamous epithelium, submucosal mucus glands 4. Stomach - The stomach is a J-shaped enlargement of the GI tract directly inferior to the diaphragm in the epigastric, umbilical, and left hypochondriac regions of the abdomen. The stomach connects the esophagus to the duodenum, the first part of the small intestine. Because a meal can be eaten much more quickly than the intestines can digest and absorb it, one of the functions of the stomach is to serve as a mixing chamber and holding reservoir.

At appropriate intervals after food is ingested, the stomach forces a small quantity of material into the first portion of the small intestine. The stomach has four main regions: the cardia, fundus, body, and pylorus: The cardia surrounds the superior opening of the stomach. The rounded portion superior to and to the left of the cardia is the fundus. Inferior to the fundus is the large central portion of the stomach, called the body. The region of the stomach that connects to the duodenum is the pylorus; it has two parts, the pyloric antrum, which connects to the body of the stomach, and the pyloric canal, which leads into the duodenum. o When the stomach is empty, the mucosa lies in large folds, called rugae (wrinkles),that can be seen with the unaided eye. The pylorus communicates with the duodenum of the small intestine via a smooth muscle sphincter called the pyloric sphincter. The concave medial border of the stomach is called the lesser curvature, and the convex lateral border is called the greater curvature. Histology Body Surface epithelium of columnar mucous cells Deeper glands of parietal (oxyntic) and endocrine cells Antrum Surface cuboidal epithelium of mucous cells Deeper loosely coiled glands of cuboidal epithelium of mucous and endocrine cells o o o o

5. Duodenum The digestive juices from the pancreas (digestive enzymes) and the gallbladder (bile) mix. The digestive enzymes break down proteins and bile and emulsify fats into micelles. The duodenum contains Brunner's glands which produce bicarbonate. In combination with bicarbonate from pancreatic juice, this neutralizes HCl of the stomach. 6. Jejunum This is the midsection of the intestine, connecting the duodenum to the ileum. It contains the plicae circulares, and villi to increase the surface area of that part of the GI Tract. Products of digestion (sugars, amino acids, fatty acids) are absorbed into the bloodstream. 7. Ileum Has villi and absorbs mainly Vitamin B12 and bile acids, as well as any other remaining nutrients. 8. Cecum Beginning of the large intestine. It receives fecal material from the ileum, and connects to the ascending colon of the large intestine. The appendix is connected to the cecum. 9. Colon Includes the Ascending Colon, Transverse Colon, Descending Colon and Sigmoid Flexure: The main function of the Colon is to absorb water, but it also contains bacteria that produce beneficial vitamins like Vitamin K. 10. Rectum The rectum acts as a temporary storage site for feces. As the rectal walls expand due to the materials filling it from within, stretch receptors from the nervous system located in the rectal walls stimulate the desire to defecate. If the urge is not acted upon, the material in the rectum is often returned to the colon where more water is absorbed. If defecation is delayed for a prolonged period, constipation and hardened feces results. 11. Anus Controls the expulsion of feces, unwanted semi-solid matter produced during digestion. Deglutition The movement of food from the mouth into the stomach is achieved by the act of swallowing, or deglutition. Deglutition is facilitated by the secretion of saliva and mucus and involves the mouth, pharynx, and esophagus. Swallowing occurs in three stages: (1) The voluntary stage, in which the bolus is passed into the oropharynx (2) The pharyngeal stage, the involuntary passage of the bolus through the pharynx into the esophagus (3) The esophageal stage, the involuntary passage of the bolus through the esophagus into the stomach. Swallowing starts when the bolus is forced to the back of the oral cavity and into the oropharynx by the movement of the tongue upward and backward against the palate; these actions constitute the voluntary stage of swallowing. With the passage of the bolus into the oropharynx, the involuntary pharyngeal stage of swallowing begins. The bolus stimulates receptors in the oropharynx, which send impulses to the deglutition center in the medulla oblongata and lower pons of the brain stem. The returning impulses cause the soft palate and uvula to move upward to close off the nasopharynx, which prevents swallowed foods and liquids from entering the nasal cavity. In addition, the epiglottis closes off the opening to the

larynx, which prevents the bolus from entering the rest of the respiratory tract. The bolus moves through the oropharynx and the laryngopharynx. Once the upper esophageal sphincter relaxes, the bolus moves into the esophagus. The esophageal stage of swallowing begins once the bolus enters the esophagus. During this phase, peristalsis, a progression of coordinated contractions and relaxations of the circular and longitudinal layers of the muscularis, pushes the bolus onward. The passage of solid or semisolid food from the mouth to the stomach takes 4 to 8 seconds; very soft foods and liquids pass through in about 1 second. Digestion Several minutes after food enters the stomach, gentle, rippling, peristaltic movements called mixing waves pass over the stomach every 15 to 25 seconds. These waves macerate food, mix it with secretions of the gastric glands, and reduce it to a soupy liquid called chyme. Few mixing waves are observed in the fundus, which primarily has a storage function. As digestion proceeds in the stomach, more vigorous mixing waves begin at the body of the stomach and intensify as they reach the pylorus. The pyloric sphincter normally remains almost, but not completely, closed. As food reaches the pylorus, each mixing wave periodically forces about 3 mL of chyme into the duodenum through the pyloric sphincter, a phenomenon known as gastric emptying. Most of the chyme is forced back into the body of the stomach, where mixing continues. The next wave pushes the chyme forward again and forces a little more into the duodenum. These forward and backward movements of the gastric contents are responsible for most mixing in the stomach. Foods may remain in the fundus for about an hour without becoming mixed with gastric juice. During this time, digestion by salivary amylase continues. Soon, however, the churning action mixes chyme with acidic gastric juice, inactivating salivary amylase and activating lingual lipase, which starts to digest triglycerides into fatty acids and diglycerides. Phases of Digestion Cephalic Phase During the cephalic phase of digestion, the smell, sight, thought, or initial taste of food activates neural centers in the cerebral cortex, hypothalamus, and brain stem. The brain stem then activates the facial (VII), glossopharyngeal (IX), and vagus (X) nerves. The facial and glossopharyngeal nerves stimulate the salivary glands to secrete saliva, while the vagus nerves stim- ulate the gastric glands to secrete gastric juice. The purpose of the cephalic phase of digestion is to prepare the mouth and stomach for food that is about to be eaten. Gastric Phase Once food reaches the stomach, the gastric phase of digestion be- gins. Neural and hormonal mechanisms regulate the gastric phase of digestion to promote gastric secretion and gastric motility. Intestinal Phase The intestinal phase of digestion begins once food enters the small intestine. In contrast to reflexes initiated during the cephalic and gastric phases, which stimulate stomach secretory activity and motility, those occurring during the intestinal phase have inhibitory effects that slow the exit of chyme from the stomach. This prevents the duodenum from being overloaded with more chyme than it can handle. In addition, responses occurring during the intestinal phase promote the continued digestion of foods that have reached the small intestine. These activities of the intestinal phase of digestion are regulated by neural and hormonal mechanisms. The Cell Cells are living structural and functional units enclosed by a membrane. All cells arise from existing cells by the process of cell division, in which one cell divides into two identical cells. Different types of cells fulfill unique roles that support homeostasis and contribute to the many functional capabilities of the human organism. Parts of the Cell 1. Plasma membrane - Forms the cells flexible outer surface, separating the cells internal environment (inside the cell) from the external environment (outside the cell). - Selective barrier that regulates the flow of materials into and out of a cell. This selectivity helps establish and maintain the appropriate environment for normal cellular activities. - Plays a key role in communication among cells and between cells and their external environment. 2. Cytoplasm - Consists of all the cellular contents between the plasma membrane and the nucleus. This compartment has two components: cytosol and organelles. - Cytosol, fluid portion of cytoplasm, contains water, dissolved solutes, and suspended particles. Surrounded by cytosol are several different types of organelles.

- Each type of organelle has a characteristic shape and specific functions. Examples include the cytoskeleton, ribosomes, endoplasmic reticulum, Golgi complex, lysosomes, peroxisomes, and mitochondria. - Parts: a. Cytosol - Medium in which many of cells metabolic reactions occur. b. Organelles - Each organelle has specific functions. c. Cytoskeleton - Maintains shape and general organization of cellular contents; responsible for cellular movements. d. Centrosome - The pericentriolar material contains tubulins, which are used for growth of the mitotic spindle and microtubule formation. e. Cilia and flagella - Cilia move fluids over a cells surface; flagella move an entire cell. f. Ribosome - Protein synthesis. g. Endoplasmic reticulum (ER) - Rough ER synthesizes glycoproteins and phospholipids that are transferred to cellular organelles, inserted into the plasma membrane, or secreted during exocytosis. Smooth ER synthesizes fatty acids and steroids; inactivates or detoxifies drugs; removes the phosphate group from glucose-6phosphate; and stores and releases calcium ions in muscle cells. h. Golgi complex - Entry (cis) face accepts proteins from rough ER; medial cisternae form glycoproteins, glycolipids, and lipoproteins; exit (trans) face modifies the molecules further, then sorts and packages them for transport to their destinations. i. Lysosome - Fuses with and digests contents of endosomes, pinocytic vesicles, and phagosomes and transports final products of digestion into cytosol; digests worn-out organelles (autophagy), entire cells (autolysis), and extracellular materials. j. Peroxisome - Oxidizes amino acids and fatty acids; detoxifies harmful substances, such as alcohol; produces hydrogen peroxide. k. Proteasome - Degrades unneeded, damaged, or faulty proteins by cutting them into small peptides. l. Mitochondrion - Site of aerobic cellular respiration reactions that produce most of a cells ATP. 3. Nucleus - A large organelle that houses most of a cells DNA. - Within the nucleus, each chromosome, a single molecule of DNA associated with several proteins, contains thousands of hereditary units called genes that control most aspects of cellular structure. - Within the nucleus are most of the cells hereditary units, called genes, which control cellular structure and direct cellular activities. Genes are arranged along chromosomes. Human somatic (body) cells have 46 chromosomes, 23 inherited from each parent. Each chromosome is a long molecule of DNA that is coiled together with several proteins. This complex of DNA, proteins, and some RNA is called chromatin. The total genetic information carried in a cell or an organism is its genome. Protein Synthesis The proteins in turn determine the physical and chemical characteristics of cells and, therefore, of the organisms formed from them. Some proteins help assemble cellular structures such as the plasma membrane, the cytoskeleton, and other organelles. Others serve as hormones, anti- bodies, and contractile elements in muscular tissue. Still others act as enzymes, regulating the rates of the numerous chemical reactions that occur in cells, or transporters, carrying various materials in the blood. Just as genome means all of the genes in an organism, proteome refers to all of an organisms proteins. In the process called gene expression, a genes DNA is used as a template for synthesis of a specific protein. First, in transcription, the information encoded in a specific region of DNA is transcribed (copied) to produce a specific molecule of RNA (ribonucleic acid). In a second process, referred to as translation, the RNA attaches to a ribosome, where the information contained in RNA is translated into a corresponding sequence of amino acids to form a new protein molecule.

DNA and RNA store genetic information as sets of three nucleotides. A sequence of three such nucleotides in DNA is called a base triplet. Each DNA base triplet is transcribed as a complementary sequence of three nucleotides, called a codon. A given codon specifies a particular amino acid. The genetic code is the set of rules that relate the base triplet sequence of DNA to the corresponding codons of RNA and the amino acids they specify. Cell Division In somatic cell division, a cell undergoes a nuclear division called mitosis and a cytoplasmic division called cytokinesis to produce two identical cells, each with the same number and kind of chromosomes as the original cell. Somatic cell division replaces dead or injured cells and adds new ones during tissue growth. Reproductive cell division is the mechanism that produces gametes, the cells needed to form the next generation of sexually reproducing organisms. This process consists of a special two- step division called meiosis, in which the number of chromosomes in the nucleus is reduced by half. Somatic Cell Division The cell cycle is an orderly sequence of events by which a somatic cell duplicates its contents and divides in two. Human cells, such as those in the brain, stomach, and kidneys, contain 23 pairs of chromosomes, for a total of 46. One member of each pair is inherited from each parent. The two chromosomes that make up each pair are called homologous chromosomes or homologs; they contain similar genes arranged in the same (or almost the same) order. When examined under a light microscope, homologous chromosomes generally look very similar. The exception to this rule is one pair of chromosomes called the sex chromosomes, designated X and Y. In females the homologous pair of sex chromosomes consists of two large X chromosomes; in males the pair consists of an X and a much smaller Y chromosome. Because somatic cells contain two sets of chromosomes, they are called diploid cells, symbolized 2n. When a cell reproduces, it must replicate (duplicate) all its chromosomes to pass its genes to the next generation of cells. The cell cycle consists of two major periods: interphase, when a cell is not dividing, and the mitotic (M) phase, when a cell is dividing. The Somatic Cell Cycle Interphase - Period between cell divisions; chromosomes not visible under light microscope. G1 Phase - Metabolically active cell duplicates organelles and cytosolic components; replication of chromosomes begins. (Cells that remain in the G1 phase for a very long time, and possibly never divide again, are said to be in the G0 phase.) S Phase - Replication of DNA and centrosomes. G2 Phase - Cell growth, enzyme and protein synthesis continues; replication of centrosomes complete.

Mitotic Phase The mitotic (M) phase of the cell cycle consists of a nuclear division (mitosis) and a cytoplasmic division (cytokinesis) to form two identical cells. The events that occur during mitosis and cytokinesis are plainly visible under a microscope because chromatin condenses into discrete chromosomes. Mitosis 1. Prophase - Chromatin fibers condense into paired chromatids; nucleolus and nuclear envelope disappear; each centrosome moves to an opposite pole of the cell. 2. Metaphase - Centromeres of chromatid pairs line up at metaphase plate. 3. Anaphase - Centromeres split; identical sets of chromosomes move to opposite poles of cell. 4. Telophase - Nuclear envelopes and nucleoli reappear; chromosomes resume chromatin form; mitotic spindle disappears. Cytokinesis - Cytoplasmic division; contractile ring forms cleavage furrow around center of cell, dividing cytoplasm into separate and equal portions.

Cell Destinies A cell has three possible destinies to remain alive and functioning without dividing, to grow and divide, or to die. Homeostasis is maintained when there is a balance between cell proliferation and cell death. The signals that tell a cell when to exist in the G0 phase, when to divide, and when to die have been the subjects of intense and fruitful research in recent years. Within a cell, there are enzymes called cyclin-dependent protein kinases (Cdks) that can transfer a phosphate group from ATP to a protein to activate the protein; other enzymes can remove the phosphate group from the protein to deactivate it. The activation and deactivation of Cdks at the appropriate time is crucial in the initiation and regulation of DNA replication, mitosis, and cytokinesis. Switching the Cdks on and off is the responsibility of cellular proteins called cyclins, so named because their levels rise and fall during the cell cycle. The joining of a specific cyclin and Cdk molecule triggers various events that control cell division. The activation of specific cyclinCdk complexes is responsible for progression of a cell from G1 to S to G2 to mitosis in a specific order. If any step in the sequence is delayed, all sub- sequent steps are delayed in order to maintain the normal sequence. The levels of cyclins in the cell are very important in determining the timing and sequence of events in cell division. For example, the level of the cyclin that helps drive a cell from G2 to mitosis rises throughout the G1, S, and G2 phases and into mitosis. The high level triggers mitosis, but toward the end of mitosis, the level declines rapidly and mitosis ends. Destruction of this cyclin, as well as others in the cell, is by proteasomes. Cellular death is also regulated. Throughout the lifetime of an organism,certain cells undergo apoptosis an orderly, genetically programmed death. In apoptosis, a triggering agent from either outside or in- side the cell causes cell-suicide genes to produce enzymes that damage the cell in several ways, including disruption of its cytoskeleton and nucleus. As a result, the cell shrinks and pulls away from neighboring cells. Although the plasma membrane remains intact, the DNA within the nucleus fragments and the cytoplasm shrinks. Phagocytes in the vicinity then ingest the dying cell. This function of phagocytes involves a receptor protein in the plasma membrane of the phagocyte that binds to a lipid in the plasma membrane of the suicidal cell. Apoptosis removes unneeded cells during fetal development, such as the webbing between digits. It continues to occur after birth to regulate the number of cells in a tissue and eliminate potentially dangerous cells such as cancer cells. Apoptosis is a normal type of cell death; in contrast, necrosis is a pathological type of cell death that results from tissue injury. In necrosis, many adjacent cells swell, burst, and spill their cytoplasm into the interstitial fluid. The cellular debris usually stimulates an inflammatory response by the immune system, a process that does not occur in apoptosis. Cell Aging Aging is a normal process accompanied by a progressive alteration of the bodys homeostatic adaptive responses. It produces observable changes in structure and function and increases vulnerability to environmental stress and disease. Although many millions of new cells normally are produced each minute, several kinds of cells in the bodyskeletal muscle cells and nerve cellsdo not divide because they are arrested permanently in the G0 phase (see page 93). Experiments have shown that many other cell types have only a limited capability to divide. Normal cells grown outside the body divide only a certain number of times and then stop. These observations suggest that cessation of mitosis is a normal, genetically programmed event. According to this view, aging genes are part of the genetic blueprint at birth. These genes have an important function in normal cells, but their activities slow over time. They bring about aging by slowing down or halting processes vital to life. Cancer Cancer is a group of diseases characterized by uncontrolled or abnormal cell proliferation. When cells in a part of the body divide without control, the excess tissue that develops is called a tumor or neoplasm. The study of tumors is called oncology. Tumors may be cancerous and often fatal, or they may be harmless. A cancerous neoplasm is called a malignant tumor or malignancy. One property of most malignant tumors is their ability to undergo metastasis, the spread of cancerous cells to other parts of the body. A benign tumor is a neoplasm that does not metastasize. Some benign tumors can be inoperable and perhaps fatal. Carcinogenesis

Malignant transformation, or carcinogenesis, is thought to be at least a three-step cellular process, involving initiation, promotion, and progression. a. Initiation Initiators (carcinogens), such as chemicals, physical factors, and biologic agents, escape normal enzymatic mechanisms and alter the genetic structure of the cellular DNA. Normally, these alterations are reversed by DNA repair mechanisms or the changes initiate programmed cellular death. Occasionally, cells escape these protective mechanisms, and permanent cellular mutations occur. These mutations usually are not significant to cells until the second step of carcinogenesis.

Abnormal Genes in Cancer Oncogenes Some genes encourage cells to multiply or 'double'. Normally, in adults, this would not happen very often. Cells would only multiply to repair damage, for example after a wound or operation. But if these genes become abnormal, they tell the cell to multiply all the time. Scientists call these genes oncogenes. This really means 'cancer genes'. Proto-oncogenes Promotes cell growth in a variety of ways. Many can produce hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and, thus, cells have a higher chance to divide excessively and uncontrollably. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, as they are critical for growth, repair and homeostasis of the body. It is only when they become mutated that the signals for growth become excessive. A gene possessing a growth-promoting role may increase carcinogenic potential of a cell, under the condition that all necessary cellular mechanisms that permit growth are activated. Tumour suppressor genes Some genes are in the cell specifically to stop the cell multiplying or doubling. If one of these 'tumor suppressor genes' becomes damaged and stops working, then the cell may carry on and on multiplying. In other words it becomes immortal, which is one of the properties of a cancer cell. The best known tumor suppressor gene is called p53. This gene normally stops cells with other damaged genes from reproducing and encourages them to destroy themselves (apoptosis). p53 is damaged or missing in most human cancers. DNA Repair Genes These genes normally repair any damage to the DNA that makes up the cell's genes. If these DNA repair genes are damaged, then other mutations are not repaired and the cell can copy the mutations when it divides and multiplies. These genes have been found to be damaged in some human cancers. b. Promotion During promotion, repeated exposure to promoting agents (cocarcinogens) causes the expression of abnormal or mutant genetics information even after long latency periods. Latency periods for the promotion of cellular mutations vary with the type of agent and the dosage of the promoter as well as the innate characteristics of the target cell. Cellular oncogenes are responsible for the vital cellular functions of growth and differentiation. Cellular protooncogenes act as an on switch for cellular growth. Proto- oncogenes are influenced by multiple growth factors that stimulate cell proliferation, such as epidermal growth factor (EGF) and transforming growth factor alpha. Another protooncogene that plays an important role in cancer development is the k-ras (KRAS2) oncogene located on chromosome 12. Just as proto-oncogenes turn on cellular growth, cancer suppressor genes turn off, or regulate, unneeded cellular proliferation. When suppressor genes mutate or lose their regulatory capabilities, malignant cells are allowed to

repro- duce. The p53 (TP53) gene is a tumor suppressor gene that is frequently implicated in many human cancers. This gene determines whether cells will live or die after their DNA is damaged. Apoptosis is the innate cellular process of programmed cell death. Alterations in TP53 may decrease apoptotic signals, thus giving rise to a survival advantage for mutant cell populations. Mutant TP53 is associated with a poor prognosis and may be associated with determining response to treatment. Once this genetic expression occurs in cells, the cells begin to produce mutant cell populations that are different from their original cellular ancestors. c. Progression During progression, the altered cells exhibit increased malignant behavior. These cells have a propensity to invade adjacent tissues and to metastasize. Growth and Spread of Cancer Cells of malignant tumors duplicate rapidly and continuously. As malignant cells invade surrounding tissues, they often trigger angiogenesis, the growth of new networks of blood vessels. Proteins that stimulate angiogenesis in tumors are called tumor angiogenesis factors (TAFs). The formation of new blood vessels can occur either by overproduction of TAFs or by the lack of naturally occurring angiogenesis inhibitors. As the cancer grows, it begins to compete with normal tissues for space and nutrients. Eventually, the normal tissue decreases in size and dies. Some malignant cells may detach from the initial (primary) tumor and invade a body cavity or enter the blood or lymph, then circulate to and invade other body tissues, establishing secondary tumors. Malignant cells resist the antitumor defenses of the body. The pain associated with cancer develops when the tumor presses on nerves or blocks a passageway in an organ so that secretions build up pressure, or as a result of dying tissue or organs. Biological Properties of Cancer Cells 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 neighboring 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). The completion of these multiple steps would be a very rare event without: Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes. Multiple Mutations A mutation to only one tumor suppressor gene would not cause cancer, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop. Usually, oncogenes are dominant alleles, as they contain gain-of-function mutations, whereas mutated tumor suppressors are recessive alleles, as they contain loss-of-function mutations. Each cell has two copies of a same gene, one from each parent, and, under most cases, gain of function mutation in one copy of a particular proto-oncogene is enough to make that gene a true oncogene, while usually loss of function mutation must happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one loss of function copy of a tumor suppressor gene can render the other copy non-functional, called the dominant negative effect. This is observed in many p53 mutations. Mutation of tumor suppressor genes that are passed on to the next generation of not merely cells, but their offspring, can cause increased likelihoods for cancers to be inherited. Members within these families have increased incidence and decreased latency of multiple tumors. The mode of inheritance of mutant tumor suppressors is that affected member inherits a defective copy from one parent, and a normal copy from another. Because mutations in tumor suppressors act in a recessive manner (note, however, there are exceptions), the loss of the normal copy creates the cancer phenotype.