Recent advances in molecular biology have revealed that a number of oncogenes (K-ras, erbB-2, and Met) and tumor suppressor genes (p53, p16, APC, and DCC) contribute to the development of pancreatic cancer. This paper reviewed the present knowledge of oncogenes and tumor suppressor genes relevant to pancreatic cancer. Further studies on molecular alterations in pancreatic cancer may lead to a
better understanding of tumor biology, offering a possibility of development of new diagnostic and therapeutic approaches in the future.膵癌の予後は惨憺たるものである｡一方で,最近の分子生物学の分野での研究の進歩により,遺伝子レベルでの異常が膵癌では数多く存在することも明らかになってきた｡膵癌の予後を改善するために,発展が期待される膵癌における遺伝子診断や遺伝子治療に向けて現在までの膵癌で明らかになった癌遺伝子(k-ras,erbB-2,Met),癌抑制遺伝子(p53,p16,APC,DDC)について,概説した

Harada, Hideo

Hasuoka, Hideaki

Ichimura, Mitsuko

Matsumura, Naoki

Mitsunobu, Fumihiro

Mizushima, Takaaki

Ochi, Koji

Tanizaki, Yoshiro

Tsurumi, Tetsuya

Yokoyama, Motohiro

Okayama University Digital Information Repository

膵癌における癌遺伝子および癌抑制遺伝子

Okayama University Scientific Achievement Repository

Oncogenes and tumor suppressor genes in pancreatic cancerOncogenes and tumor suppressor genes inpancreatic cancerKoji Oehi, Naoki Matsumura, Mitsuko Ichimura, TakaakiMizushima, Hideo Harada, Hideaki Hasuoka l ), MotohiroYokoyama2), Tetsuya Tsurumi2), Fumihiro Mitsunobu3), YoshiroTanizaki3)Dept Laboratory Medicine, Okayama UniversityMedical School, Katsuyama Hospital!), OkayamaRed Cross Hospital2), Misasa Medical Branch,Okayama University Medical School3)82Abstract: Recent advances In molecular biology have revealed that a number ofoncogenes (K-ras, erbB-2, and Met) and tumor suppressor genes (p53, p16, APC, andDCC) contribute to the development of pancreatic cancer. This paper reviewed thepresent knowledge of oncogenes and tumor suppressor genes relevant to pancreaticcancer. Further studies on molecular alterations In pancreatic cancer may lead to abetter understanding of tumor biology, offering a possibility of development of newdiagnostic and therapeutic approaches In the future.Key Word: Pancreatic cancer, oncogene, tumor suppressor gene, genetic mutationIntroductionPancreatic cancer is an important cause of deathsfrom cancers in the developed countries includingJapan. It has remained to elucidate its biologicalcharacteristics and also to establish the method for itsearly detection. Recent advances in molecular biologyhas revealed that a number of oncogenes and tumorsuppressor genes contribute to the development ofpancreatic cancer. Improvement in its prognosis maybe enabled by early molecular diagnosis and gene-targeting treatment in the future. This paper reviewsthe present knowledge of oncogenes and tumor supp-ressor genes relevant to pancreatic cancer.K-rasRas gene family consists of three kinds of genes:N-ras, H-ras, and K-ras. Each of the genes encode a21-kDa protein with GTPase involved in cell growthand differentiation I). If K-ras was mutated, the proteinseems to lose GTPase activity and thereby to affect thetumorigenic process by altering the signal transductionpathway across the membrane2). K-ras point mutationat codon 12 has been detected in 80-90% of pancreaticductal adenocarcinoma3-6).83 Oncogenes and tumor suppressor genes in pancreatic cancerIn the model of colorectal carcinoma, ras mutationsare considered to be associated with progression of theneoplastic process, because 10% of adnomas <1.0 cmin size have as compared with 50% of adenomas>1.0cm in size have ras mutations?). In pancreatic cancer,K-ras mutation is not related to clinical course,metastasis, or prognosis6.8). K-ras point mutation isknown to be often detected in the ductal cell hy-perplasias adjacent to pancreatic cance~). It is co-ntroversial whether these lesions are precancerous9). Inanimal models,· weekly injection of nitrosamine in-duced K-ras mutations in 28% of hyperplastic lesions,48% of papillary hyperplastic lesions, 78% of car-cinomas-in-situ, and 80% of invasive cancers of thepancreas. These results suggested that K-ras mutationis an early event in the multi-step progression topancreatic neoplasmlO).K-ras mutations in pure pancreatic juice (PPJ) havebeen identified in attempts to diagnose pancreaticcancer in early stageI1-13). Some investigatorsI4,15)reported that K-ras mutation in PPJ preceded thedefinitive diagnosis of pancreatic cancer. We alsoexperienced a case of small pancreatic cancer diagnos-ed by serial follow-up studies promptly by a positiveK-ras point mutation in ppJI6). However, K-ras muta-tion from PPJ was reported to be detected in 37-44%of patients with chronic pancreatitis1?18), and long-term follow-up of patients with chronic pancreatitisrevealed that no pancreatic cancer developed in mu-tation-positive patients17). Further studies are needed toexplore the clinical implication of detection of K-rasmutations in the early diagnosis of pancreatic cancer.erbB-2The erbB-2 (Her-2/neu) oncogene encodes a trans-membrane protein with homology to the epidermalgrowth factor receptor. The erbB-2 protein is over-epressed in 25-58% of pancreatic cancersI9-23). Fre-quency of erbB-2 protein overexpression depends ontumor differentiation. Lower expression of erbB-2 wasobserved in poorly differentiated adenocarcinomathan in moderate or well-differentiated adenocar-cinoma23.24). As the erbB-2 protein is also overexpress-ed in mucinous hyperplasia of the pancreatic duct, theerbB-2 is suggested to be a potential mediator ofgrowth factor-related signal transduction in pancreaticduct24). Overexpression of erbB-2 was reported to beinversely related to the survival of patients withpancreatic cancerO).The positive rate of serum c-erbB-2 protein wasreported as from 25% to 35%19,22). Although Okada22)reported that serum c-erbB-2 correlated with me-tastases and decreased survival rate in patients withpancreatic cancer, liver function influenced its serumlevelsI9).MetThe c-Met oncogene encodes MET protein which isthe receptor for hepatocyte growth factor (HGF)25).Although MET immunoreactiveity was mild in acinar,ductal, and islet cells of the normal pancreas was , itwas intense in many of the duct-like cancer cell ofhuman pancreatic adenocarcinoma was intense26).Since concomitant overexpreesion of HGF was ob-served in the pancreatic cancer, HGF is suggested toplay a role in proliferation of pancreatic cancer as theautocrine or paracrine26.2?). MET immunoreactivityleads to a significantly longer survival than ne-gative/focal staining28). These data suggest that Metmight have an important pathogenetic role during theearly stages of development of pancreatic cancer8).p53The p53 gene, which is localized on the short arm ofchromosome 17, encodes p53 protein. The p53 proteinis believed to playa prominent role in the regulation ofcell cycles. After the identification of the p53, earlyobservation suggested that p53 might function as anoncogene, because overexpression of p53 appeared tocause oncogenic transformation of cells. Several laterstudies, however, defined the normal function of thep53 to be anti-oncogenic because p53-null micedeveloped tumors much more29.30). The p53 gene isinactivated in diverse human cancers by allelic de-letions, point mutations that result from amino-acidOncogenes and tumor suppressor genes in pancreatic cancer 84substitutions, and rearrangement31.32l. p53 gene mu-tations are observed in almost half of pancreaticadenocarcinomas8).Relationship between p53 mutations and survival inpancreatic carcinoma is controversia8). Redston et al.33)found that there was no significant difference inoverall survival between patients with and thosewithout p53 mutations. In contrast, Nakamori et al.34)found that the median survival (6.2 months) of thepatients with p53 mutations was significantly shorterthan that (15.0 months) of those without p53 mu-tations.Immunohistochemical examination for p53 proteinwas known to be useful to detect p53 gene mutation,because mutated p53 protein had a considerably longerhalf-life than wild p53 protein. Further studies haverevealed that p53 protein accumulation is not alwaysdependent on p53 gene mutation35). Bourdon et al.reported that stabilization of the p53 protein dependedalso on mechanisms other than p53 gene mutation,such as binding other molecules of cellular origin35l. Inaddition, Maacke et al36). reported that p53 proteinoverexpression in cytological specimens of PPJ sam-ples was found in 59% of patients with pancreatitisand 67% of patients with pancreatic cancer: Ove-repressed p53 in pancreatitis appears to be wild-typep53 and may result from DNA damage occurringduring chronic inflammation.p161CDKN2(MTS1 )The p16 in the chromosome 9p21 encodes a proteinwhich inhibits the activity of the cyclin-dependentkinase 4 (cd4)37). pl6 is called multiple tumor supp-ressor 1 (MTS1) because inactivation of p16 wasobserved in many cancers38). In pancreatic cancer,Caldas et al.39) reported that pl6 was deleted ho-mozygously in 15 (41%) and mutated in 14 (38%) of37 pancreatic carcinomas.The p16 gene mutations were reported to be morefrequent in culture cell line than in primarytumors40.4I). The effect of p16 mutations on survival inpancreatic cancer has not been reported yet.APCAPe, located on the chromosome 5q21, is thecausative gene of non-polipotic familial adenoma ofthe colon. APC is known to participate in the earlystage of multi-step carcinogesis of the colon cancer42l.This g~ne was found to encode for a cytoplasmicprotein with sequence homology to intermediate fila-ment proteins such as myosin and keratin43). AlthoughHorii et al.44) found that APe mutaations was observedin 40% of pancreatic cancer, another two studies45.46)showed frequencies below 3% of APe mutations wasbelow 3%. Further studies are needed on APe gene inpancreatic cancer.DCCApproximately 70% of colon cancers have deletionsin the region of 18q21, which was later found to be thelocus of DCC (deleted in colorectal carcinomagene)42). Hohne et al.47) reported that 63.2% ofpancreatic cancers had DCC mutations. 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膵癌における癌遺伝子および癌抑制遺伝子

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