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shed from the bowel wall into the lumen. This recyclingprocess begins in the crypts of Lieberku ¨ hn, at the base of microvilli.

Underneath this mucosal layer lies the submucosa, thestrength layer of the bowel. This layer contains bloodvessels, lymphatics and terminal nerve fibres. It is animportant layer with regards to the genesis of cancer

because once a tumour has invaded into this region of thebowel wall it can gain entrance to the blood supply andlymphatic system, permitting distant spread throughoutthe body. Thus, the earliest stage of colon cancer, termedDukes’stage A, represents a stage at which cancer is limitedto the submucosa and has not spread to lymph nodes ordistant organ sites. The likelihood of survival followingresection of these early stage cancers is very high. Dukes’ Btumours have invaded into and through the muscular layerof the bowel walland thus carryan increasedrisk of distantspread; Dukes’ C tumours have already spread to regionallymph nodes.

Epidemiology

While the incidence of colon cancer varies widely fromcountry to country throughout the world, colon cancer is acommon disease in the United States. Adenocarcinoma of the colon and rectum accounted for approximately 35 000cases and 55 000 deaths in 1999 (Landis et al ., 1999). Whilethe mean age of diagnosis is approximately 67 years of age,the incidence rises steadily from age 50 to age 80. Thusfewer than 10% of cancers are diagnosed before age 40.The majority of colon cancers are not inherited but rather

are considered sporadic, having developed from anaccumulation of mutations throughout the course of alifetime. Approximately 10% of colon cancers are con-sidered inherited: a genetic mutation in genomic deoxyr-ibonucleic acid (DNA) (involving all cells in the body) hasbeenpassedon from one generationto another. In additionto inherited cancers, familial cancer predispositions mayexist that are independent of the hereditary nonpolyposiscolon cancer (HNPCC) and familial adenomatous poly-posis (FAP) diseases. To date, these predisposing factorsare not well defined.

Current data suggest that epidemiological risk factorsfor cancer, other than genetic risk factors, include dietary

components, such as the amount of fat and fibre in the die(Cummings and Southgate, 1999) and perhaps the intakof calcium (Bresalier, 1999; Faivre and Bonithon-Kopp1999; Mobarhan, 1999), vitamins of the antioxidant clas(Slattery et al ., 1999), and nonsteroidal antiinflammatoragents such as aspirin and more specific inhibitors of cyclooxygenase (Lipsky, 1999). The risk of colon cance

increases with age, the history of previous polyps ocancer, the family history of cancer, and the history olong-standing inflammatory bowel disease, includinulcerative colitis and even Crohn disease.

Genetics

Whereas cancer is a genetic disease, only 10% of colocancers are actually inherited from family members. Ifact, the majority of colon cancers are considered sporadiin nature and are derived from accumulated genet

changes. These changes occur within the epithelial cellof the mucosal surface of the bowel wall throughout thlifespan of the person. Once a critical number of genetichanges have occurred (usually 5–6), a cancer madevelop. A genetic model for the development of colocancer has recently evolved (Vogelstein and Kinzler, 1993this is largely due to extensive gains in our understandingohuman genetics, as a direct result of the human genomproject (Figure 2).

Our current understanding suggests that colon cancer ia disease of disrupted growth control. Early genetalterations occur in the colonic epithelial cells lining thbowel wall. The genetic changes involve mutations o

alterations in the genetic code responsible for producinspecific proteins. These mutational alterations or deletionresult in the production of malformed proteins, which arabsent or can no longer function normally.As a result, celmay be ‘turned on’ to grow without limits and may resisnormal mechanisms that result in cell death, a process ocellular suicide called apoptosis.

We now know that two basic types of important growtgenes are affected in cancer, oncogenes and tumousuppressor genes. Oncogenes represent the mutated formof preexisting normal genes, called protooncogenes, whichave normal growth-stimulatory functions in the cell. Onlwhen these genes are mutated in specific regions can the

Normal mucosa Early adenoma Carcinoma MucosaLate adenoma

Genetic alteration necessary

APC RAS p53 DCC/DPC4 (Smad4)

MCC

Oncogene activationTumour suppressor deletion

Figure 2 Multistep model of colon cancer progression includes alterations in both oncogenes and tumour suppressor genes.

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take on constitutively active (always turned on) growthfunctions. Tumour suppressorgenes are the second class of genes that are affected in the genesis of colon cancer. Whilethe specific function and identity of many of these genes inthis class are not yet identified, it is clear that specific genesare deleted in the development of cancers and that theirabsence resultsdirectly in tumour formation.In the normal

cell, protooncogenes provide growth stimulus and tumoursuppressor genes provide growth control. In the tumourcell, mutated protooncogenes and mutated or deletedtumour suppressor genes permit continuous uncheckedgrowth stimuli.

Two of the earliest genes affected in the development of colon cancer are the adenomatous polyposis coli (APC )gene and the RAS gene (Fearon and Vogelstein, 1990). TheAPC gene wasidentified in a group of patients with familialcolon cancer characterized by hundreds to thousands of adenomatous polyps throughout the colon (familialpolyposis), each with malignant potential. In thesepatients, the APC gene represents a tumour suppressor

gene. When both copies of this gene are affected or lost,colon polyps will develop, frequently at a very early age.The mechanisms for the formation of polyps and cancer inpatients with familial polyposis has been validated bymurine models in which the APC gene has been mutated orcompletely knocked out. In these models, mice developnumerous adenomatous polyps throughout the smallbowel,with some in the colon.While these polyps generallydo not develop into invasive cancers, they frequently bleedand lead to obstruction of the bowel. These mice provide avaluable resource for the testing of new drugs that mightprevent polyps or cancer. For example, aspirin and othernonsteroidal agents have been demonstrated to reduce the

incidence of polyps in mice, verifying the observation inhumans that drugs like these may be beneficial inpreventing cancer. Interestingly, this gene is also the mostcommonly affected gene (up to 95% of cases) innoninherited forms of colon cancer, otherwise known assporadic colon cancer. Because it is the first gene to beaffected in the development of colon cancer, it has beencalled the ‘gatekeeper’. Until recently, its role in thedevelopment of colon cancer has remained elusive but nowthere is evidence to suggest thatthe mutated APC gene mayactivate the transcription of two genes downstream, MYC (He et al ., 1998) and CYCLIN D through the action of proteins such as b-catenin and TCF/lef-1. The protein

products of these genes, c-Myc and cyclin D, have beenimplicated in cellular transformation and the growth of cancer.

In common with APC , the RAS gene is also thought tobe involved in the early transition from normal epitheliumto premalignant tissue. The RAS gene is commonlymutated (up to 50% of cases) in premalignant colonpolyps. It is one of the most well understood protoonco-genes. We now know that it has a normal function inactivating downstream genes in signal transaction cascades

through phosphorylation events. When the RAS gene imutated, it is constitutively activated in a guanosintriphosphate (GTP)-locked form, such that it is alwaycapable of phosphorylating downstream targets, targetcritical to the growth control of the cell. It results in aactivated Ras pathway, whereby Ras activates downstream proteins such as Raf, MEK, MAPK and Erk, wit

the end result being increased transcriptional activity in thnucleus. This transcriptional activity is presumed tmaintain continuous growth characteristic of the cancecell. More recently, the mechanism by which Ras attached to the cytoplasmic membrane has been elucdated. A farnesyl group is transferred to the Ras protein ban enzyme called farnesyltransferase, which is now thintense target of drugdiscovery efforts (farnesyltransferasinhibitors, FTIs). FTIs are already in clinical trials thaseek to inhibit this enzyme and thus prohibit thinteraction of Ras with the cytoplasmic membrane, thereby blocking the growth effects of Ras. For signatransduction cascades, location is critical, and withou

membrane association even mutated Ras becomes inactivwithout farneslyation.

Once a number of early genetic changes have occurredadditional changes may snowball. This process is termegenetic instability. The predisposition to cellular divisioresults in increased potential for mutational events, ansubsequent genetic changes can accumulate. One promnent genetic change occurs in the p53 gene. The p53 gene the most commonly mutated gene in human cancer (up t50% of all human cancers contain a p53 mutation(Koshland, 1993). Because its deletion results in spontaneous tumour formation in both animal models and ihumans, it is thought to represent a tumour suppresso

gene where both alleles or genetic copies must be affectedtresult in a phenotypic change. The normal function of p5appears to be related to DNA repair following a toxiinsult.

WhenDNA is damaged, normal or wild-type p53 signathe cell to self-destruct, a form of cellular suicide calleapoptosis. When p53 is mutated, DNA damage may gunrepaired and unrecognized, resulting in the contributioof damaged DNA to subsequent generations of cells. Thlack of recognition of abnormal cells, with their associateelimination, is a critical failure common to cancer cellMutations spontaneously developing subsequent to th p53 mutation may theoretically be accumulated rapidl

without correction. This is precisely why tumours aadvanced stages seem to have accumulated larger numberof genetic defects, engendering the capacity for advancerates of growth invasion and distant metastasis or spread

Other genes and chromosomal defects that have beereported include the MCC tumour suppressor gene locateon chromosome 5 (Gayther et al ., 1993; Kopnin, 1993), ithe DCC (Chen etal ., 1999; Saito etal ., 1999; Sturlan etal1999) and DPC-4 tumour suppressor genes located ochromosome 18. The DPC-4 gene is now also known a

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ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net



Smad-4 and may be regulated in part by the transforminggrowth factor b (TGFb) receptor pathway (Korchynskyiet al ., 1999). The latter genes appear to be associated withmore advanced stages of disease. More recently, a genesuch as the SRC oncogene has also been identified asparticipating in the process of advanced tumour growth(Irby etal ., 1999).It is believed that mutations in genes such

as SRC , which are generally uncommon, are possible in amilieu of the tumour cell with multiple mutations capableof continuous unchecked growth and DNA repair. SRCoverexpression or activation may be responsible forantiapoptotic activity and increased angiogenesis, bothof which may contribute to tumour development andprogression.

Familial Adenomatous Polyposis

FAP is a rare inherited disease characterized by the

development of hundreds to thousands of adenomatouspolyps in the colon by early adulthood. Less than 1% of allcolon cancers are secondary to FAP. Without treatment,100% of patients with this disease will develop invasivecolon cancer with the risk of metastatic spread. Recently,the genetic lesion responsible for this disease has beenidentified (Kinzler et al ., 1991; Su et al ., 1992; Cao et al .,1999; Norheim Andersen et al ., 1999). The APC gene hasbeen found to be mutated, such that one copy or allele isdefective, generally resulting in a shortened proteinproduct. Interestingly, this is the same gene in which amissense mutation has been found in 6% of AshkenaziJews (a different, less severe mutation conferring a slightly

increased risk of colon cancer) and in most tumours frompatients with sporadic or noninherited forms of coloncancer. These common genetic links suggest an importantrole for the APC gene in the development of colon cancer.More recently, a specific role for the APC gene product incolon cancer cells has been elucidated. A pathway initiatedby the mutated APC gene product appears to lead to theincreased production of c-Myc, a transcription factorlinked to cellular transformation and growth. In addition,the APC pathway may lead to the increased production of cyclin D1, resulting in the stimulation of cell growth via thecell cycle.

Because FAP is an inherited genetic disease associated

with mutation of genomic DNA, the entire mucosalsurface of the large intestine is at risk for the formationof polyps and cancer. Moreover, these patients carry therisk of developing polyps in the duodenum. In addition,variants of the familial polyposis syndrome includeGardner syndrome and Turcot syndrome, presumed alsotobelinkedtodefectsofthe APC gene. Because of this risk,treatment is aimed at the prophylactic removal of the entirecolon and rectum at an early age, before the formation of any cancerous changes. Treatment options include total

proctocolectomy, with permanent colostomy or witreconstruction by an ileoanal pull-through procedure.

Hereditary Nonpolyposis Colon Cancer

HNPCC is another form of hereditary cancer, accountinfor up to 10% of colon cancer cases. It has also beereferred to as Lynch syndromes I and II. Patients with thidisease tend to have numerous relatives diagnosed witcolon cancer, some before the age of 50 – or approximatel10–15 years before the appearance of most colon cancer

Unlike FAP, this disease has been linked to mutations iproofreading genes coding for mismatch repair enzymeThese genes include MLH1, MSH2, PMS1, PMS(Bronner et al ., 1994; Nicolaides et al ., 1994). This diseasis also characterized by the replication error phenotyp(RER) which results in micosatellite instability. Whiinstability at multiple microsatellite loci can screen fo

affected individuals, clinical criteria (Amsterdam) (Syngaetal ., 1999) are nowalso available for attempting to predicthe risk of harbouring this disease. The name for thdisease is somewhat a misnomer because the majority opatients actually harbour a number of polyps, althougmany fewer than seen in FAP. This disease may manifesitself in early adulthood and result in the development oinvasive cancer. It has also been associated with thformation of tumours in other organs and is predominantly linked to formation of right-sided colon cancersGenetic testing for the disease is now available for patientmeeting specific clinical and family history criteria.

Detection

Because the colon is deep within the abdominal cavity, itcommon for a developing cancer to go undetected untsignificant symptoms develop. Generally, a tumour musbleed, resulting in blood in the stool, or must obstruct thbowel lumen, resulting in abdominal pain, before it can bdetected without routine screening measures. It is preciselfor this reason that many patients present with largtumours or with advanced disease that has alreadmetastasized to distant organ sites at the time of diagnosiThis is a disappointing fact because the majority o

tumours take years to develop, during which time thermay be the opportunity for early detection and possiblprevention.

Early detection by screening is generally the best meanof detecting this disease in a curable stage. The concept oscreening to reduce cancer mortality has gained significanfavour in the management of breast cancer, where routinscreening mammography has shifted the identification othe majority of breast cancers to earlier stages than wapreviously possible. While in the past colon cance

Colon Cancer




screening was limited to the use of an uncomfortable air-contrast barium enema, current fibreoptic technology haspermitted development of flexible sigmoidoscopes andcolonoscopes, which can be used to inspect the entiremucosal surface of the large intestine without significantdiscomfort. Current screening recommendations from theAmerican Cancer Society (Table 1) recommend an annual

faecal occult blood test, and sigmoidoscopy every 5 years,starting at age 50, for low-risk adults. For those with a first-degree relative diagnosed with colon cancer, a totalcolonoscopic examination is recommended, starting atage 40 or 10 years before the age at which the youngest first-degree relative developed cancer.

Tumour markers are generally ineffective in detectingcarcinoma of large intestine and are therefore notrecommended for screening purposes. Once diagnosedwith colon cancer, however, measurements of carcinoem-bryonic antigen (CEA) may be useful in predicting thepresence of distant metastatic disease (serum le-vels4 10ngml2 1) for determining the effectiveness of a

surgical resection. Computed tomography is generally notuseful for screening purposes but is quite effective indetermining the extent of local or metastatic disease.

Treatment

The treatment plan for colon cancer is generally based onthe state of the disease, the location of the disease and thefunctional status of the patient. Thus, attempts atpreoperative staging can be useful in the proper manage-ment of the colon cancer patient. The primary treatment

modality for colon cancer is surgery. Most surgical

procedures are performed via an exploratory laparotomyalthough laparoscopic procedures conducted withoularge systems are also being performed on an experimentbasis. Surgical extirpation of the disease is frequently thmost important component of treatment and may be thonly form of treatment required. These operations arnearly always accomplished without the use of a perma

nent colostomy, and only rarely are temporary colostomieneeded. Wide local excision with resection of associateregional lymphatics and lymph nodes is the underlyinprinciple of all surgical treatment of the colon. In moscircumstances, the risk of local recurrence is not related tthe extent of a mucosal margin (proximal or distal) burather it is often related to the extent of a radial marginThis status is justified by the fact that the anastomotioccurrences are actually uncommon. On the other handlocal recurrences and local metastatic spread to thperitoneum and the omentum (termed carcinomatosiare more common. This problem relates to the frequenfull-thickness penetration of the bowel wall by colo

cancers. Cancers that invade all layers of the bowel wamaycontinue to invade adjacent organs and local tissues ospread throughout the abdomen, much like the seeds of dandelion in the wind. The surgeon faced with local diseaswill generally attempt to resect it all en bloc; even adjacenorgans, such as the uterus, ovaries or bladder, may bcompletely or partially removed. Once the disease hametastasized to lymph nodes beyond the local basin, or tdistant organ sites such as the liver or the lungs, it is rarelcurable by surgical intervention alone. Exceptions includlimited metastatic disease (fewer than four lesions) to thliver or lungs without extrahepatic or extrapulmonardisease.

Once the disease has spread to lymph nodes or to distanorgan sites, chemotherapy is generally incorporated inttreatment plans. Adjuvant chemotherapy is generallrecommended for patients with nodal disease (Dukestage C). Current regimens generally utilize 6 months oadjuvant chemotherapy with S-phase-specific cytotoxidrugs, including 5-fluorouracil and leucovorin. Whilpatients with full-thickness tumours but without evidencof total disease (Dukes’ B) carry the risk of distanmetastasis, chemotherapy has not been proven to beffective. Recently, however, immune modulation has beedemonstrated to have potentially beneficial effects in thsubgroup of patients. Modulation may take the form o

vaccination with radiated, autologous tumour cells icombination with the immune adjuvant bacillus CalmetteGue ´ rin (BCG). Recent trials are also underway with aantibody called 17-1A directed against tumour cells, whicmay have some benefit in these stages of disease (Dukes’ Band C).

For patients with metastatic disease to distant sites, sucas the liver or lungs, systemic chemotherapy is generallindicated and includes drugs such as 5-fluorouracileucovorin and ironotecan. While 5-fluorouracil has bee

Table 1 American Cancer Society guidelines for the early

detection of colon or rectal cancer

Starting at age 50, both men and women should have:

. yearly faecal occult blood test, and flexible sigmoido-

scopy and digital rectal examination every 5 years

or

. colonoscopy and digital rectal examination every

10 years

or

. double-contrast barium enema and digital rectal

examination every 5– 10 yearsPeople should begin screening earlier and have it more

often if they have any of these risk factors:

. a strong family history of colon or rectal cancer or polyps

(mother, father, sisters or brothers)

. a family history of hereditary colorectal cancer

syndromes

. a personal history of colon or rectal cancer or chronic

inflammatory bowel disease (having already had

colorectal cancer)

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ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net



the mainstay of colon cancer chemotherapy for 30 years,novel therapeutic interventions are currently in clinicaltrials. These agents include drugs to inhibit blood vesselformation (antiangiogenesis) and drugs to target specificabnormal proteins within the colon cancer cell, such asRas.

References

Bresalier RS (1999) Calcium, chemoprevention, and cancer: a small step

forward (a long way to go). Gastroenterology 116: 1261–1263.

Bronner CE,BakerSM, Morrison PT etal . (1994)Mutation in theDNA

mismatch repair gene homologue hMLH1 is associated with

hereditary non-polyposis colon cancer. Nature 368: 258–261.

Cao X, Eu KW, Seow-Choen F and Cheah PY et al . (1999) Germline

mutations are frequent in the APC gene but absent in the beta-catenin

gene in familial adenomatous polyposis patients. Genes Chromosomes

and Cancer 25: 396–398.

Chen YQ, Hsieh JT, Yao F et al . (1999) Induction of apoptosis and G2/

M cell cycle arrest by DCC. Oncogene 18: 2747–2754.

Cummings JH and Southgate DA (1999) Dietary fiber and colorectal

cancer [letter; comment]. New England Journal of Medicine 340: 1925–

1926.

Faivre J and Bonithon-Kopp C (1999) Chemoprevention of colorectal

cancer. Recent Results in Cancer Research 151: 122–133.

Fearon E and Vogelstein B (1990) A genetic model for colorectal

tumorigenesis. Cell 61: 759–767.

Gayther S, Wells D, Gulati K et al . (1993) Germline rearrangement of

MCC and APC detected by pulsed field gel electrophoresis and

fluorescent in situ hybridization (publishederratum appears in Annals

of Human Genetics 1993; 57:311). Annalsof Human Genetics 57: 169–

178.

He TC, Sparks AB, Rago C et al . (1998) Identification of c-MYC as a

target of the APC pathway. Science 281: 1509–1512.

Irby RB, Mao W, Coppola D etal . (1999)Activating SRC mutation in a

subset of advanced human colon cancers. Nature Genetics 21: 187–

190.

Kinzler KW, Nilbert MC, SuLK etal . (1991) Identification of FAP locu

genes from chromosome 5q21. Science 253: 661–665.

Kopnin B (1993) Genetic events responsible for colorectal tumorigen

esis: achievements and challenges. Tumori 79: 235–243.

Korchynskyi O, Landstrom M, Stoika R et al . (1999) Expression o

Smad proteins in human colorectal cancer. International Journal o

Cancer 82: 197–202.

Koshland DE Jr (1993) Molecule of the year (editorial). Science 26

1953.Landis SH, Murray T, Bolden S and Wingo PA (1999) Cancer statistic

1999. CA: A Cancer Journal for Clinicians 49: 8–31.

Lipsky PE (1999) The clinical potential of cyclooxygenase-2-specifi

inhibitors. American Journal of Medicine 106: 51S–57S.

Mobarhan S (1999) Calcium and the colon: recent findings. Nutritio

Reviews 57: 124–126.

Nicolaides NC, Papadopoulos N, Liu B et al . (1994) Mutations of tw

PMS homologues in hereditary nonpolyposis colon cancer. Natu

371: 75–80.

Norheim Andersen S, Lovig T, Fausa O and Rognum TO et al . (199

Germlineand somatic mutationsin exon 15of theAPCgene andK-r

mutations in duodenal adenomas in patients with familial adenoma

touspolyposis. Scandinavian Journal of Gastroenterology 34: 611–61

Saito M,Yamaguchi A,Goi T etal . (1999)Expression of DCCproteini

colorectal tumors and its relationship to tumor progression an

metastasis. Oncology 56: 134–141.

Slattery ML, Potter JD, Samowitz W, Schaffer D and Leppert M (199

Methylenetetrahydrofolate reductase, diet, and risk of colon cance

Cancer Epidemiology, Biomarkers and Prevention 8: 513–518.

Sturlan S, Kapitanovic S, Kovacevic D e t al . (1999) Loss o

heterozygosity of APC and DCC tumor suppressor genes in huma

sporadic colon cancer. Journal of Molecular Medicine 77: 316–321.

Su LK, Kinzler KW, Volgelstein B et al . (1992) Multiple intestin

neoplasia caused by a mutation in the murine homolog of the AP

gene (published erratum appears in Science 1992; 256: 1114). Scienc

256: 668–670.

Syngal S, Fox EA, Li C et al . (1999) Interpretation of genetic test resul

for hereditarynonpolyposis colorectalcancer: implications for clinic

predisposition testing. JAMA 282: 247–253.

Vogelstein B and Kinzler KW (1993) The multistep nature of cance

Trends in Genetics 9: 138–141.

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