Intestinal wall

An increase in the total surface of the mucosa reflects the absorptive function of the small intestine. Four degrees of folding amplify the absorptive surface area of the mucosa (see Figure 16-2): (1) the plicae circulares (circular folds; also known as the valves of Kerkring), (2) the intestinal villi, (3) the intestinal glands, and (4) the microvilli on the apical surface of the lining epithelium of the intestinal cells (enterocytes).

A plica circularis is a permanent fold of the mucosa and submucosa encircling the intestinal lumen.

Plicae appear about 5 cm distal to the aborad outlet of the stomach, become distinct where the duodenum joins the jejunum, and diminish in size progressively to disappear halfway along the ileum.

The intestinal villi are finger-like projections of the mucosa covering the entire surface of the small intestine. Villi extend deep into the mucosa to form crypts ending at the muscularis mucosae. The length of the villi depends on the degree of distention of the intestinal wall and the contraction of smooth muscle fibers in the villus core.

Crypts of Lieberkühn, or intestinal glands, are simple tubular glands that increase the intestinal surface area. The crypts are formed by invaginations of the mucosa between adjacent intestinal villi.

The muscularis mucosae is the boundary between the mucosa and submucosa (see Figure 16-3). The muscularis consists of inner circular smooth muscle and outer longitudinal smooth muscle. The muscularis is responsible for segmentation and peristaltic movement of the contents of the small intestine (Figure 16-4). A thin layer of loose connective tissue is covered by the visceral peritoneum, a serosal layer lined by a simple squamous epithelium, or mesothelium. The parietal peritoneum covers the inner surface of the abdominal wall.

Figure 16-4 Intestinal motility: Muscular contraction patterns

Microcirculation of the small intestine

A difference from the microcirculation of the stomach (see Figure 15-8 in Chapter 15, Upper Digestive Segment) is that the intestinal submucosa is the main distribution site of blood and lymphatic flow (see Figure 16-3).

Branches of the submucosal plexus supply capillaries to the muscularis and intestinal mucosa. Arterioles derived from the submucosal plexus enter the mucosa of the small intestine and give rise to two capillary networks: (1) the villus capillary plexus supplies the intestinal villus and upper portion of the crypts of Lieberkühn; and (2) the pericryptal capillary plexus supplies the lower half of the crypts of Lieberkühn.

A single blind-ending central lymphatic vessel, the lacteal, is present in the core of a villus. The lacteal is the initiation of a lymphatic vessel that, just above the muscularis mucosae, forms a lymphatic plexus whose branches surround a lymphoid nodule in the mucosa-submucosa. Efferent lymphatic vessels of the lymphoid nodule anastomose with the lacteal and leave the digestive tube through the mesentery, together with the blood vessels.

Innervation and motility of the small intestine

Motility of the small intestine is controlled by the autonomic nervous system. The intrinsic autonomic nervous system of the small intestine, consisting of the submucosal plexus of Meissner and myenteric plexus of Auerbach, is similar to that of the stomach (see Figure 15-9 in Chapter 15, Upper Digestive Segment).

Neurons of the plexuses receive intrinsic input from the mucosa and muscle wall of the small intestine and extrinsic input from the central nervous system through the parasympathetic (vagus nerve) and sympathetic nerve trunks.

Contraction of the muscularis is coordinated to achieve two objectives (see Figure 16-4): (1) To mix and mobilize the contents within an intestinal segment. This is accomplished when muscular contraction activity is not coordinated and the intestine becomes transiently divided into segments. This process is known as segmentation. (2) To propel the intestinal contents when there is a proximal (orad) contraction coordinated with a distal (aborad; Latin ab, from; os, mouth; away from the mouth) relaxation. When coordinated contraction-relaxation occurs sequentially, the intestinal contents are propelled in an aborad direction. This process is known as peristalsis (Greek peri, around; stalsis, constriction).

Histologic differences between the duodenum, jejunum, and ileum

Each of the three major anatomic portions of the small intestine—the duodenum, jejunum, and ileum—has distinctive features that allow recognition under the light microscope (Figure 16-5).

Figure 16-5 Histologic differences: Duodenum, jejunum, and ileum

The duodenum extends from the pyloric region of the stomach to the junction with the jejunum and has the following characteristics: (1) It has Brunner’s glands in the submucosa. Brunner’s glands are tubuloacinar mucous glands producing an alkaline secretion (pH 8.8 to 9.3) that neutralizes the acidic chyme coming from the stomach. (2) The villi are broad and short (leaflike shape). (3) The duodenum is surrounded by an incomplete serosa and an extensive adventitia. (4) The duodenum collects bile and pancreatic secretions transported by the common bile duct and pancreatic duct, respectively. The sphincter of Oddi is present at the terminal ampullary portion of the two converging ducts. (5) The base of the crypts of Lieberkühn may contain Paneth cells.

The jejunum has the following characteristics: (1) It has long finger-like villi and a well-developed lacteal in the core of the villus. (2) The jejunum does not contain Brunner’s glands in the submucosa. (3) Peyer’s patches in the lamina propria may be present but they are not predominant in the jejunum. Peyer’s patches are a characteristic feature of the ileum. (4) Paneth cells are found at the base of the crypts of Lieberkühn.

The ileum has a prominent diagnostic feature: Peyer’s patches, lymphoid follicles (also called nodules) found in the mucosa and part of the submucosa. The lack of Brunner’s glands and the presence of shorter finger-like villi—when compared with the jejunum—are additional landmarks of the ileum. As in the jejunum, Paneth cells are found at the base of the crypts of Lieberkühn.

Villi and crypts of Lieberkühn

The intestinal mucosa, including the crypts of Lieberkühn, are lined by a simple columnar epithelium containing four major cell types (Figure 16-6): (1) absorptive cells, or enterocytes, (2) goblet cells, (3) Paneth cells, and (4) enteroendocrine cells. Stem cells, Paneth cells, and enteroendocrine cells are found in the crypts of Lieberkühn (see Figure 16-6).

Figure 16-6 Epithelial cells of the villus and crypt of Lieberkühn

Absorptive intestinal cells, or enterocytes

The absorptive intestinal cell or enterocyte has an apical domain with a prominent brush border (also called a striated border), ending on a clear zone, called the terminal web, which contains transverse cytoskeletal filaments. The brush border of each absorptive cell contains about 3000 closely packed microvilli, which increase the surface luminal area 30-fold.

The length of a microvillus ranges from 0.5 to 1.0 μm. The core of a microvillus (Figure 16-7) contains a bundle of 20 to 40 parallel actin filaments cross-linked by fimbrin and villin. The actin bundle core is anchored to the plasma membrane by formin (protein of the cap), myosin I, and the calcium-binding protein calmodulin. Each actin bundle projects into the apical portion of the cell as a rootlet, which is cross-linked by an intestinal isoform of spectrin to an adjacent rootlet. The end portion of the rootlet attaches to cytokeratin-containing intermediate filaments. Spectrin and cytokeratins form the terminal web. The terminal web is responsible for maintaining the upright position and shape of the microvillus and anchoring the actin rootlets.

Figure 16-7 Intestinal epithelium

A surface coat or glycocalyx consisting of glycoproteins as integral components of the plasma membrane covers each microvillus.

The microvilli, forming a brush border, contain intramembranous enzymes, including lactase, maltase, and sucrase (Figure 16-8). These oligosaccharides reduce carbohydrates to hexoses, which can be transported into the enterocyte by carrier proteins. A genetic defect in lactase prevents the absorption of lactose-rich milk, leading to diarrhea (lactose intolerance). Therefore, the brush border not only increases the absorptive surface of enterocytes but is also the site where enzymes are involved in the terminal digestion of carbohydrates and proteins.

Figure 16-8 Digestion and absorption of proteins and carbohydrates

Final breakdown of oligopeptides, initiated by the action of gastric pepsin, is extended by pancreatic trypsin, chymotrypsin, elastase, and carboxypeptidases A and B. Enterokinase and aminopeptidase, localized in the microvilli, degrade oligopeptides into dipeptides, tripeptides, and amino acids before entering the enterocyte across symporter channels together with Na⁺. Cytoplasmic peptidases degrade dipeptides and tripeptides into amino acids, which then diffuse or are transported by a carrier-mediated process across the basolateral plasma membrane into the blood.

The absorption of lipids involves the enzymatic breakdown of dietary lipids into fatty acids and monoglycerides, which can diffuse across the plasma membrane of the microvilli and the apical plasma membrane of the enterocyte. Details of the process of fat absorption are depicted in Figure 16-9.

Figure 16-9 Digestion and absorption of lipids

Goblet cells

Goblet cells are columnar mucus-secreting cells scattered among enterocytes of the intestinal epithelium (see Figure 16-7).

Goblet cells have two domains: (1) a cup- or goblet-shaped apical domain containing large mucus granules that are discharged on the surface of the epithelium and (2) a narrow basal domain, which attaches to the basal lamina and contains the rough endoplasmic reticulum in which the protein portion of mucus is produced. The Golgi apparatus, which adds oligosaccharide groups to mucus, is prominent and situated above the basally located nucleus.

The secretory product of goblet cells contains glycoproteins (80% carbohydrate and 20% protein) released by exocytosis. On the surface of the epithelium, the mucus hydrates to form a protective gel coat to shield the epithelium from mechanical abrasion and bacterial invasion.

Enteroendocrine cells

In addition to its digestive function, the gastrointestinal tract is the largest diffuse endocrine gland in the body.

We have already studied the structural and functional features of enteroendocrine cells in the stomach (see Chapter 15, Upper Digestive Segment). As in the stomach, enteroendocrine cells secrete peptide hormones controlling several functions of the gastrointestinal system. The location and function of gastrin-, secretin-, and cholecystokinin-secreting cells are summarized in Figure 16-10.

Figure 16-10 Roles of gastrin, secretin, and cholecystokinin in digestion

Intestinal tight junction barrier

Intestinal tight junctions link adjacent enterocytes and provide a barrier function impermeable to most hydrophilic solutes in absence of specific transporters. Tight junctions establish a separation between the intestinal luminal content and the mucosal immune function that occurs within the lamina propria. Plasma cells, lymphocytes, eosinophils, mast cells and macrophages are present in the intestinal lamina propria.

Claudin and occludin are two transmembrane proteins of tight junctions that regulate solute permeability of the transcellular pathway. Flux of dietary proteins and bacterial lipopolysaccharides across leaky tight junctions can increase in the presence of tumor necrosis factor–α and interferon-γ, two proinflammatory cytokines that affect tight junction integrity. Many diseases associated with intestinal epithelial dysfunction, including inflammatory bowel disease and intestinal ischemia, are linked to increased levels of tumor necrosis factor.

A minor tight junction barrier defect can allow bacterial products or dietary antigens to cross the epithelium and enter the lamina propria. Antigens can bind to Toll-like receptor of dendritic cells. Dendritic cells migrate to a local mesentery lymph node and the antigen is presented to naïve T cells by the major histocompatibility complex to determine their differentiation into T helper 1 (Th1) and T helper 2 (Th2) cells that relocate to the lamina propria (Figure 16-11). Th1 cells produce the proinflammarory cytokines tumor necrosis factor and interferon-γ. Th2 cells downregulate the proinflammatory activity of Th1 cells by secreting interleukin-10. If the mucosa immune cell activation response proceeds unchecked, proinflammatory cytokines will continue enhancing further leakage across the tight junction barrier, a condition leading to intestinal chronic inflammatory diseases.

Figure 16-11 Intestinal tight junction barrier

Peyer’s patches

Peyer’s patches—the main component of the gut-associated lymphoid tissue (GALT)—are specialized lymphoid follicles found in the intestinal mucosa and part of the submucosa (see Box 16-A). A Peyer’s patch displays two main components (Figure 16-12): (1) a dome and (2) a germinal center.

Figure 16-12 Peyer’s patch: A component of the gut-associated lymphoid tissue (GALT)

Peyer’s patches are lined by the follicle-associated epithelium (FAE), consisting of M cells and enterocytes—both derived from stem cells present in the intestinal glands. Antigens in the intestinal lumen activate Toll-like receptors, expressed by enterocytes (see Box 10-A in Chapter 10, Immune-Lymphatic System), leads to the production of B cell-activating factor and cytokines that stimulate the production of immunoglobulin (Ig) A by plasma cells.

The dome separates the Peyer’s patch from the overlying surface epithelium and contains B cells expressing all immunoglobulin isotypes, except IgD. The germinal center contains IgA-positive B cells, CD4⁺ T cells, and antigen-presenting cells (dendritic cells). A few plasma cells are present in the Peyer’s patches.

The main components of the FAE are the M cell (Figure 16-13), a specialized epithelial cell that takes up antigens into protease (cathepsin E)-containing vesicles, and the dendritic cell, extending cytoplasmic processes across epithelial tight junctions. Antigens are transported by transcytosis to adjacent intercellular spaces and presented to immunocompetent cells (B cells).

Figure 16-13 Peyer’s patch: Cellular immune surveillance system of the intestinal tract

The apical domain of M cells has short micro folds (hence the name M cell). The basolateral domain of M cells forms intraepithelial pockets, the home site for a subpopulation of intraepithelial B cells.

Intestinal antigens, bound to immunoglobulin receptors on the surface of B cells, interact with antigen-presenting cells at the dome region. Processed antigens are presented to follicular dendritic cells and CD4⁺ T cells to initiate an immune reaction.

Clinical significance: Targeting mucosal vaccine vectors to M cells

M cells are unique among epithelial cells in that endocytosed antigens enter a transepithelial vesicular transport pathway and are released at pocket membrane sites to induce an immune response. This property has stimulated current interest in developing mucosal vaccine vectors to induce protective mucosal immune responses.

This host defense strategy can eventually lead to the production of secretory IgA dimer (Figure 16-14) and proteins from Paneth cells (Figure 16-15) to clear the mucosal surface of pathogens.

Figure 16-14 IgA dimer: Molecular immune surveillance of the intestinal tract

Figure 16-15 Paneth cells: Adaptive antimicrobial immunity

Plasma cells and secretory IgA dimer

Plasma cells secrete IgA dimers into the intestinal lumen, the respiratory epithelium, the lactating mammary gland, and salivary glands. Most plasma cells are present in the lamina propria of the intestinal villi, together with lymphocytes, eosinophils, mast cells, and macrophages.

IgA molecules secreted by plasma cells are transported from the lamina propria to the intestinal lumen by a transcytosis mechanism consisting of the following steps (see Figure 16-14): (1) IgA is secreted into the lamina propria as a dimeric molecule associated with a joining peptide, called the J chain. (2) The IgA dimer binds to a specific receptor, called the poly-immunoglobulin (poly-Ig) receptor, expressed on the basolateral surfaces of the intestinal epithelial cell. The poly-Ig receptor has an attached extracellular secretory component. (3) The IgA–poly-Ig receptor–secretory component complex is internalized and transported across the cell to the apical surface of the epithelial cell (transcytosis). (4) At the apical surface, the complex is cleaved enzymatically and the IgA-secretory component complex is released into the intestinal lumen. The secretory component protects the dimeric IgA from proteolytic degradation. (5) IgA antibodies prevent the attachment of bacteria or toxins to epithelial cells. (6) Excess IgA dimers diffuse from the lamina propria into the bloodstream and are excreted into the intestinal lumen via the bile.

Paneth cells

All intestinal cells, Paneth cells in particular, secrete antimicrobial proteins to limit bacteria-enterocyte contact. Most of these proteins kill bacteria directly by enzymatic degradation of the bacterial wall or by disrupting the bacterial inner membrane. A group of antimicrobial proteins deprive bacteria of essential heavy metal such as iron.

Antimicrobial proteins are retained in the intestinal mucus blanket. Therefore, the mucus layer protects the enterocyte surface by two mechanisms: (1) by creating a barrier that limits direct access of luminal bacteria to the epithelium, and (2) by concentrating antimicrobial proteins near the enterocyte surface. Antimicrobial proteins are virtually absent from the luminal content.

Paneth cells are present at the base of the crypts of Lieberkühn and have a lifetime of about 20 days. The pyramid-shaped Paneth cells have a basal domain containing the rough endoplasmic reticulum. The apical region contains numerous protein granules (see Figure 16-15. Figure 16-16).

Figure 16-16 Lower half of an intestinal gland (crypt of Lieberkühn)

The three major products contained in the granules of Paneth cells are (1) TNF-α, (2) lysozyme, and (3) a group of proteins known as defensins or cryptidins. The expression of a subset of antimicrobial proteins is controlled by bacterial signals. For example, Toll-like receptor in enterocytes control the expression of the antimicrobial C-type lectin REG3γ (for regenerating islet-derived protein 3γ) in the small intestine. NOD2 (for nucleotide-binding oligomerization domain-containing protein 2) controls the expression of defensins.

Defensins are produced continuously or in response to microbial products or pro inflammatory cytokines (for example, TNF-α). As mentioned in our discussion on the intestinal tight junction barrier, TNF-α is a proinflammatory cytokine produced in response to diverse infectious agents and tissue injury.

The antimicrobial effect of defensins is based on the lack of cholesterol and abundance of negatively charged phospholipids of the membrane of microorganisms. Defensins disrupt the microbial membrane by inserting themselves within the phospholipid membranes. Defensins enhance the recruitment of dendritic cells to the site of infection and facilitate the uptake of antigens by forming defensin-antigen complexes.

Lysozyme is a proteolytic enzyme that cleaves peptidoglycan bonds. Peptidoglycan is present in bacteria but not in human cells. Lysozyme-treated bacteria swell and rupture as the result of the entrance of water into the cell. Defensins have an antimicrobial effect by increasing the membrane permeability of a target organism (parasites or bacteria) through the formation of ion channels.

Clinical significance: Inflammatory bowel diseases

Inflammatory bowel disease includes ulcerative colitis and Crohn’s disease. Both are clinically characterized by diarrhea, pain, and periodic relapses. Ulcerative colitis can affect the mucosa of the large intestine. Crohn’s disease affects any segment of the intestinal tract.

Crohn’s disease is a chronic inflammatory process involving the terminal ileum but is also observed in the large intestine. Inflammatory cells (neutrophils, lymphocytes, and macrophages) produce cytokines that cause damage to the intestinal mucosa (Figure 16-17).

Figure 16-17 Crohn’s disease

The initial alteration of the intestinal mucosa consists in the infiltration of neutrophils into the crypts of Lieberkühn. This process results in the destruction of the intestinal glands by the formation of crypt abscesses and the progressive atrophy and ulceration of the mucosa.

The chronic inflammatory process infiltrates the submucosa and muscularis. Abundant accumulation of lymphocytes forms aggregates of cells, or granulomas, a typical feature of Crohn’s disease.

Major complications of the disease are occlusion of the intestinal lumen by fibrosis and the formation of fistulas in other segments of the small intestine, and intestinal perforation. Segments affected by Crohn’s disease are separated by normal stretches of intestinal segments.

The cause of Crohn’s disease is unknown. There is increasing evidence suggesting that the disease arises from dysregulated interactions between microorganisms and the intestinal epithelium. Patients with intestinal bowel disease have an increased number of bacteria associated with the epithelial cell surface, suggesting a failure of mechanisms that limit direct contact between microorganisms and the epithelium. A contributing factor is the reactive immune response of the intestinal mucosa determined by an abnormal signaling exchange with the resident bacteria (microbiota). In genetically susceptible individuals, inflammatory bowel disease occurs when the mucosal immune machinery regards the microbiota (microorganisms present in normal and healthy individuals) as pathogenic and triggers an immune response.

As discussed (see Figure 16-11), cytokines produced by helper T cells within the intestinal mucosa cause a proinflammatory response that characterizes inflammatory bowel disease. In Crohn’s disease, type 1 helper cells (Th1 cells) produce TNF-α and interferon-γ. Because TNF-α is a proinflammatory cytokine, antibodies to this cytokine are being administered to patients with Crohn’s disease to attenuate proinflammatory activity.

Clinical significance: Malabsorption syndromes

Malabsorption syndromes are characterized by a deficit in the absorption of fats, proteins, carbohydrates, salts, and water by the mucosa of the small intestine.

Malabsorption syndromes can be caused by (1) abnormal digestion of fats and proteins by pancreatic diseases (pancreatitis or cystic fibrosis) or lack of solubilization of fats by defective bile secretion (hepatic disease or obstruction of the flow of bile into the duodenum); (2) enzymatic abnormalities at the brush border, where disaccharidases and peptidases cannot hydrolyze carbohydrates (lactose intolerance) and proteins, respectively; and (3) a defect in the transepithelial transport by enterocytes.

Malabsorption syndromes affect many organ systems. Anemia occurs when vitamin B_12, iron, and other cofactors cannot be absorbed. Disturbances of the musculoskeletal system are observed when proteins, calcium, and vitamin D fail to be absorbed. A typical clinical feature of malabsorption syndromes is diarrhea.

Clinical significance: Hirschsprung’s disease

We discussed in Chapter 8, Nervous Tissue, that during formation of the neural tube, neural crest cells migrate from the neuroepithelium along defined pathways to tissues, where they differentiate into various cell types. One destination of neural crest cells is the alimentary tube, where they develop the enteric nervous system. The enteric nervous system partially controls and coordinates the normal movements of the alimentary tube that facilitate digestion and transport of bowel contents.

The large intestine, like the rest of the alimentary tube, is innervated by the enteric nervous system receiving impulses from extrinsic parasympathetic and sympathetic nerves and from receptors within the large intestine.

The transit of contents from the small intestine to the large intestine is intermittent and regulated at the ileocecal junction by a sphincter mechanism: When the sphincter relaxes, ileal contractions propel the contents into the large intestine.

Segmental contractions in an orad-to-aborad direction move the contents over short distances. The material changes from a liquid to a semisolid state when it reaches the descending and sigmoid colon. The rectum is usually empty. Contraction of the inner anal sphincter closes the anal canal. Defecation occurs when the sphincter relaxes as part of the rectosphincteric reflex stimulated by distention of the rectum.

Delayed transit through the colon leads to severe constipation. An abnormal form of constipation is seen in Hirschsprung’s disease (congenital megacolon) caused by the absence of the enteric nervous system in a segment of the distal colon (Figure 16-23). This condition, called aganglionosis, is the result of an arrest in the migration of cells from the neural crest, the precursors of the intramural ganglion cells of the plexuses of Meissner and Auerbach.

Figure 16-23 Hirschsprung’s disease (congenital megacolon)

Aganglionosis is caused by mutations affecting the RET gene encoding receptor tyrosine kinase. RET signaling is required for the formation of Peyer’s patches (see Box 16-A), for the migration of neural crest cells into the distal portions of the large intestine and for differentiation into neurons of the enteric nervous system.

The permanently contracted aganglionic segment does not allow the entry of the contents. An increase in muscular tone in the orad segment results in its dilation, thus generating a megacolon or megarectum. This condition is apparent shortly after birth when the abdomen of the infant becomes distended and little meconium is eliminated.

The diagnosis is confirmed by a biopsy of the mucosa and submucosa of the rectum showing thick and irregular nerve bundles, abundant acetylcholinesterase detected by immunohistochemistry and a lack of ganglion cells. Surgical removal of the affected colon segment is the treatment of choice but intestinal dysfunction may persist after surgery.

Clinical significance: Familial polyposis gene and colorectal tumorigenesis

Colorectal tumors develop from a polyp, a tumoral mass that protrudes into the lumen of the intestine. Some polyps are non-neoplastic and are relatively common in persons 60 years and older. Polyps can be present in large number (100 or more) in familial polyposis syndromes such as familial adenomatous polyposis and the Peutz-Jeghers syndrome. Familial polyposis is determined by autosomal dominant mutations, in particular in the APC (adenomatous polyposis coli) gene. Mutations in the APC gene have been detected in 85% of colon tumors, indicating that, as with the retinoblastoma (Rb) gene, the inherited gene is also important in the development of the sporadic form of the cancer.

The APC gene encodes APC protein with binding affinity to microtubules and β-catenin, a molecule associated with a catenin complex linked to E-cadherin (discussed in Chapter 1, Epithelium) and also a component of nuclear transcription complexes.

When β-catenin is not part of the catenin α, β, γ complex, free β-catenin interacts with DNA binding proteins of a family of transcription factor proteins called T cell factor–lymphoid enhancer factor (Tcf3-Lef) to form a transactivator complex that stimulates transcription of immediate gene targets (Figure 16-24).

Figure 16-24 APC (adenomatous polyposis coli) and cancer of the colon

When free β-catenin binds to the glycogen synthase kinase 3β (GSK3β)-axin-APC complex, it is phosphorylated by GSK3β. Phosphorylated β-catenin is subsequently recognized by a ubiquitin ligase complex that catalyzes the attachment of polyubiquitin chains to phosphorylated β-catenin. Polyubiquitin conjugates of β-catenin are rapidly degraded by the 26S proteasome. The lack of β-catenin inactivates the β-catenin–Tcf–Lef pathway. A mutation in the APC gene results in a defective protein that reduces cell-cell contact and increases the pool of available β-catenin. Essentially, APC is a tumor suppressor gene.

The APC gene is also a major regulator of the Wnt pathway, a signaling system expressed during early development and embryogenesis (see Chapter 3, Cell Signaling). The Wnt pathway has an important function in the development of neural crest–derived cells. Wnt proteins can inactivate GSK3β, prevent the phosphorylation of β-catenin, and abrogate its destruction by the 26S proteasome. Consequently, an excess of β-catenin translocates to the cell nucleus to affect gene transcription.

A defective β-catenin pathway can overexpress the microphthalmia-associated transcription factor (MITF). We discussed in Chapter 11, Integumentary System, the significance of MITF in the survival and proliferation of melanoma cells.

Hereditary nonpolyposis colon cancer (HNPCC) is an inherited form of colorectal cancer caused by mutations in genes involved in the repair of DNA mismatch. HNPCC is an example of a cancer syndrome caused by mutations in DNA repair proteins. Patients with the HNPCC syndrome do not show the very large number of colon polyps typical of the familial polyposis syndrome, but a small number of polyps occur frequently among gene carriers.

Concept mapping

Lower Digestive Segment