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Abstract

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

Pancreatic ductal adenocarcinoma is one of the most fatal malignancies. Intensive investigation of molecular pathogenesis might lead to identifying useful molecules for diagnosis and treatment of the disease. Pancreatic ductal adenocarcinoma harbors complicated aberrations of alleles including losses of 1p, 6q, 9p, 12q, 17p, 18q, and 21q, and gains of 8q and 20q. Pancreatic cancer is usually initiated by mutation of KRAS and aberrant expression of SHH. Overexpression of AURKA mapping on 20q13.2 may significantly enhance overt tumorigenesity. Aberrations of tumor suppressor genes synergistically accelerate progression of the carcinogenic pathway through pancreatic intraepithelial neoplasia (PanIN) to invasive ductal adenocarcinoma. Abrogation of CDKN2A occurs in low-grade/early PanIN, whereas aberrations of TP53 and SMAD4 occur in high-grade/late PanIN. SMAD4 may play suppressive roles in tumorigenesis by inhibition of angiogenesis. Loss of 18q precedes SMAD4 inactivation, and restoration of chromosome 18 in pancreatic cancer cells results in tumor suppressive phenotypes regardless of SMAD4 status, indicating the possible existence of a tumor suppressor gene(s) other than SMAD4 on 18q. DUSP6 at 12q21-q22 is frequently abrogated by loss of expression in invasive ductal adenocarcinomas despite fairly preserved expression in PanIN, which suggests that DUSP6 works as a tumor suppressor in pancreatic carcinogenesis. Restoration of chromosome 12 also suppresses growths of pancreatic cancer cells despite the recovery of expression of DUSP6; the existence of yet another tumor suppressor gene on 12q is strongly suggested. Understanding the molecular mechanisms of pancreatic carcinogenesis will likely provide novel clues for preventing, detecting, and ultimately curing this life-threatening disease. (Cancer Sci 2005)

Abbreviations: 
GTP

guanosine triphosphate

HPDE

human pancreatic duct epithelium

LOH

loss of heterozygosity

MAPK

mitogen-activated protein kinase

MMCT

microcell-mediated chromosome transfer

PanIN

pancreatic intraepithelial neoplasia

PDA

pancreatic ductal adenocarcinoma

SRO

smallest region of overlap

TSG

tumor suppressor gene.

Pancreatic cancer is the fifth leading cause of cancer death in men, the sixth in women, in Japan and other developed countries.(1) The five-year survival rate for pancreatic cancer is very low, less than 10%,(1) but both the incidence and mortality of pancreatic cancer are increasing.(2) This information indicates that current interventions to prevent, diagnose, and cure the disease are far from satisfactory. We need to develop novel and efficient procedures to medicate patients with this cancer; this need has driven many researchers to intensive investigations of the molecular mechanisms of the development and progression of pancreatic cancer to detect the molecular clues that are valuable for the invention of novel procedures. This review focuses on the elucidation of current knowledge about the molecular insights of pancreatic carcinogenesis.

Genomic analysis of pancreatic cancer

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

Pancreatic ductal adenocarcinoma (PDA), the most common type of pancreatic cancer, harbors complicated aberrations of chromosomal alleles, that is, losses in multiple chromosome arms, including 1p, 3p, 4q, 6q, 8p, 9p, 12q, 17p, 18q, and 21q, and gains in 8q and 20q.(3) The aberrations are very characteristic for comparing PDA with other types of cancer, most of which reveal aberrations in fewer numbers of chromosomal regions. The regions where losses occur are suggested to harbor tumor suppressor genes (TSGs); those where gains occur, to harbor oncogenes. Detailed analyses of loss of heterozygosity (LOH) using microsatellite markers indicates several particularly lost regions in 1p, 6q, 9p, 12q, 17p, and 18q; three smallest regions of overlap (SROs) in 6q(4) and two in 12q(5,6) were identified. However, no conclusive candidate TSG has been identified. In 1p, several candidate genes such as TP73, RIZ, ICAT, and RUNX3 were analyzed,(7–10) but alterations in these genes were rather rare in pancreatic cancer. Future efforts will disclose the conclusion of TSGs in these chromosome arms.

Significant concordance of LOHs were found between 6q and 17p and between 12q and 18q, and LOHs of 12q, 17p and 18q were reported to be associated with poor prognosis of patients with PDA.(11) A study using probes to detect aberrations of specific chromosomal regions including 8q24, 9p21, 17p13, 18q21 and 20q11 by fluorescence in situ hybridization in cells in pancreatic juice taken from patients undergoing endoscopic retrograde cholangiopancreatography was performed to test the diagnostic relevance of these allelic aberrations.(8) Aberrations of copy numbers were detected in 70% of patients with pancreatic neoplasms, but no aberrations were detected in any of the patients without them. These results showed that these characteristic allelic aberrations can be used as diagnostic markers for pancreatic cancer.(12)

Promoting molecules

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

The great majority of PDA cases harbor a gain-of-function mutation of KRAS.(13) RAS is a GTP-binding protein involved in growth factor-mediated signal transduction pathways.(14) The mutations of KRAS are observed at codons 12, 13 and 61, and the overall frequencies are more than 90% in PDAs. The mutations result in the generation of a constitutively active form of RAS. The constitutively active RAS intrinsically binds to GTP and gives uncontrolled stimulatory signals to downstream cascades involving mitogen-activated protein kinases (MAPKs). Mutations of KRAS are frequently observed in pancreatic ductal precursor lesions/pancreatic intraepithelial neoplasia (PanIN). The consistent mutations of KRAS in PanIN as well as in PDA indicate that the activation of pathways involving RAS is essential for pancreatic carcinogenesis. However, the mutations of KRAS do not appear to be sufficient for the development of PDA. Pancreas-specific endogenous expression of active Kras, KrasG12D, in genetically engineered mice results in the development of PanIN frequently, but the development of PDA very exceptionally.(15) Transfection of the activated KRAS in HPDE cells, the immortalized near-diploid ductal cells derived from normal human pancreas, show partially transformed phenotypes.(16) These results suggest that additional genetic and/or epigenetic events, in addition to the activation of KRAS, are necessary for the development of PDA.

SHH is frequently overexpressed in PDAs as well as in PanINs.(17,18) Pancreas-specific overexpression of SHH in genetically engineered mice resulted in the development of PanIN.(17) Gene expression profiling of early PanIN indicated the aberrant expression of foregut markers, which was suggested to be a result of activation of the Hedgehog pathway in the lesion.(19) Suppression of the Hedgehog pathway showed suppressive phenotypes of the cultured pancreatic cancer cells.(17) Hedgehog is a family molecule regulating cell fates in embryogenesis in Drosophila as well as in vertebrates. Activation of the Hedgehog signaling pathway by sporadic mutations or in familial conditions such as Gorlin's syndrome is known to be associated with tumorigenesis in skin, the cerebellum, and skeletal muscle.(18) These pieces of information suggest that the activation of the Hedgehog pathway plays a role at the initial step of the development of PanIN, subsequently progressing to PDA.

Gain of copy number of 20q is frequently observed in PDAs, which indicates a possible existence of oncogene(s) in this chromosome arm.(3) Several candidate oncogenes have been isolated, including AURKA locating on 20q13.2.(20)AURKA encodes AURKA/STK15/Aurora-A kinase, an essential molecule involved in regulating the functions of centrosomes, spindles, and kinetochores, which are required for proper mitosis of cells.(17) AURKA is overexpressed in various cancer tissues, including PDA, which is associated with a higher grade of tumor and a poorer survival of patients with cancer.(17–23) This overexpression can induce checkpoint disruption by interfering with p53 function and tetraploidization, possibly leading to aneuploidy;(24,25) these may be some of the critical causes for a worsened prognosis. Depletion of AURKA by RNA interference in human pancreatic cancer cells resulted in marked growth suppression in vitro, abolishment of tumorigenesity in vivo, and synergistic enhancement of cytotoxicity of taxanes, chemotherapeutic agents interfering with the functions of the mitotic spindle.(26) These observations indicate that the overexpression of AURKA plays important roles in the progression of PDA.

Aberrations of suppressive pathways

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

As discussed in the previous section, PDAs have lost multiple allelic regions hemizygously or homozygously. These regions of loss may harbor tumor suppressor genes. Homozygous deletion of 9p21 is frequently observed in PDA. This region harbors CDKN2A/INK4A/p16. This gene is inactivated frequently in PDA by deletion or mutation.(27) Even in PDAs harboring wild-type CDKN2A, expression of the gene is transcriptionally silenced by hypermethylation of the promoter, which indicates that CDKN2A is inactivated in virtually all PDAs(28) (Fig. 1). Expression of CDKN2A is lost in moderate/low-grade PanINs.(29,30) Loss of Cdkn2a/Ink4a in endogenous KrasG12D-expressing mice results in the development of a poorly differentiated sarcomatoid locally invasive carcinoma that is an unusual form in human PDA.(31) The CDKN2A is a cyclin-dependent kinase inhibitor. It binds to CDK4 and prevents interaction between CDK4 and CCND1, which induces cell cycle arrest at G1 phase in cooperation with normal RB function.(32) These pieces of information suggest that the loss of CDKN2A occurs early and enhances the oncogenic potential of activating KRAS in pancreatic carcinogenesis.

image

Figure 1. Aberrations of multiple molecules in pancreatic ductal adenocarcinoma (P). Note loss of expressions of CDKN2A (panel b), SMAD4 (panel d), and DUSP6 (panel e) and abnormal accumulation of TP53 (panel c). Panel a, hematoxylin and eosin staining. N, normal duct.

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PDAs have frequently lost 17p13.(5) The region harbors TP53/p53, the gene frequently mutated in PDAs.(33) The mutations have been observed as missense or nonsense ones; the former type is more common than the latter in human malignant tumors, including PDA.(34) TP53 is a DNA binding protein functioning as a transcription factor modulating molecules pertaining to variety of functions mainly involved in cell cycle arrest and apoptosis.(35) The missense mutations of TP53 are preferentially observed in its DNA binding domain, which abrogates the binding capacity. The missense-mutated TP53 proteins abnormally accumulated in the nucleus by suppressed turnover, which is observed as if the protein were overexpressed immunohistochemically (Fig. 1). Abnormal accumulation of TP53 is frequently observed in high grade/late PanIN lesions as well.(30) Targeted concomitant endogenous expression of Trp53R172H and KrasG12D to the mouse pancreas revealed the cooperative development of invasive and metastatic ductal carcinoma characterized by loss of wild type allele of Trp53 and diverse chromosomal instability, which recapitulates human PDA.(36) Missense mutated Trp53 can inhibit Trp63 and Trp73 activity and increase its transformation activity.(37) These observations suggest that the aberration of TP53 function under activated KRAS in pancreatic ductal cells induces chromosomal instability and additional genetic aberrations that can advance carcinogenic pathways to invasive ductal carcinoma.

Familial pancreatic cancer

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

Some tumors develop in a hereditary manner; examples include retinoblastoma, familial adenomatous polyposis, breast cancer, neurofibromatosis, and multiple endocrine neoplasia. Such familial syndromes gave valuable clues for the isolation of responsible genes.(38) The isolation of BRCA2 on chromosome 13 was accelerated by the identification of a homozygous deletion in pancreatic cancer,(39) but the great majority of pancreatic cancers do not harbor mutation in this gene. Several familial pancreatic cancer pedigrees have been reported and positive linkage analysis was detected,(40,41) but isolation of the responsible gene(s) is yet to be accomplished.

Impact of loss of chromosome 18q

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

Chromosome 18q is frequently deleted hemizygously and/or homozygously in a vast majority of PDAs.(3,5)SMAD4 was identified in the homozygously deleted region at 18q21.1.(42) SMAD4 is abrogated in approximately 50% of PDAs either by homozygous deletion or mutation.(42,43) Expression of SMAD4 is frequently lost in high-grade/late PanIN lesions as well as in PDA(30,44) (Fig. 1). SMAD4 is a signal mediator involved in the transforming growth factor-β signaling pathway that plays important roles in the negative regulation of cell proliferation, as well as induction of extracellular matrices, angiogenesis, and immune suppression.(45) SMAD4 comprises a hetero-multimer with SMAD2 and SMAD3, which translocates into the nucleus and functions as a transcription factor cooperating with p300/CBP.(45) Restoration of SMAD4 in SMAD4-deleted pancreatic cancer cells resulted in no alteration of cell growth in vitro but the abolition of tumorigenesity in immunodeficient mice due to suppression of angiogenesis, which suggests that SMAD4 functions as a suppressor of tumorigenesis by interfering with interactions between epithelial cells and stromal cells.(46)

Although loss of heterozygosity at chromosome 18q is an overwhelming event in PDAs, occurring in 80–90% of them, the complete SMAD4 inactivation, namely a two-hit mutation, is found in approximately 50%.(42) In intraductal papillary-mucinous neoplasms of the pancreas, one of the precursor types of neoplasms of PDA, loss of 18q is frequently observed despite exclusive preservations of expressions of SMAD4.(12,47) Homozygous deletion telomeric of the SMAD4 locus is observed in some fractions of PDAs.(48) These observations indicate a possible existence of unknown TSG(s) on 18q. To test this possibility, introduction of an additional copy of chromosome 18 into cultured pancreatic cancer cells with or without SMAD4 inactivation was performed by microcell-mediated chromosome transfer (MMCT).(49) The transferred cells revealed a marked growth retardation, loss of ability for anchorage-independent growth, and modest invasiveness in vitro. The in vivo tumorigenic ability of the transferred cells was significantly reduced. These results were obtained unanimously throughout the transferred cells despite their different SMAD4 functional status.(49) Moreover, the chromosome 18-transferred cells revealed marked reductions of metastatic ability in experimental in vivo models.(50) These observations strongly suggest that a TSG(s), particularly a metastasis-suppressing gene(s), other than SMAD4, exists on 18q, and it is involved in pancreatic carcinogenesis.

Tumor suppressor on chromosome 12q

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

Loss of heterozygosity at chromosome 12q is a frequent aberration in PDAs.(5) Fine mapping of LOH by microsatellite analysis employing markers encompassing the entire long arm of chromosome 12 at every few centi-morgans uncovered two SROs; one at 12q21 and the other at 12q22-q23.1.(6) The mapping of expressed sequence tags in and around these regions to clone candidate tumor suppressor genes resulted in the isolation of DUSP6/MKP-3 at 12q21-q22.(51) No possible function-affecting mutations were observed, but the DUSP6 mRNA expressions was strongly suppressed.(51) As shown in Fig. 1, expression of DUSP6 was markedly reduced and/or abolished in PDAs, especially in the poorly differentiated type, despite its fairly good preservation in PanINs.(52) The abrogation of expression of DUSP6 is associated with hypermethylation of a possible control region of the DUSP6 gene.(53) DUSP6 is a dual specificity phosphatase that specifically binds and dephosphorylates MAPK1, which makes a feedback loop to regulate a physiological activity of MAPK1/ERK2.(54) The cultured pancreatic cancer cells lacking expression of DUSP6 tend to show constitutively active MAPK1, which suggests that loss of function of DUSP6 could induce constitutive activation of MAPK1.(52) Exogenous overexpression of DUSP6 in DUSP6-abrogated pancreatic cancer cells results in growth suppression and the induction of apoptosis.(52) These observations indicate that epigenetic silencing of DUSP6 is one of the crucial causes of the pathogenesis of PDAs.

How can the abrogation of DUSP6 be interpreted in pancreatic carcinogenesis and progression? As already noted, 80–90% of PDAs harbor the gain-of-function mutation of KRAS.(9)KRAS encodes RAS, which acts as a molecular switch of downstream signal cascades including RAF1-MAP2K-MAPK1. The mutated KRAS generates a constitutively active RAS that hyperstimulates the downstream cascades. In the negative feedback loop manner, the hyperactivated MAPK1 would activate DUSP6, which in turn can suppress the extraordinarily activated MAPK1. However, the abrogation of DUSP6 may result in loss of the feedback loop, which can lead to constitutive activation of MAPK1. The constitutive active MAPK1 may translocate into the nucleus and activate transcription factors that drive numerous effector genes, which could contribute to uncontrolled cell growth and cellular oncogenesis (Fig. 2). From these points of view, DUSP6 functions as a tumor suppressor in the pancreatic carcinogenic pathway that is exclusively surmounted under the activated RAS phenotype.(55) The tumor suppressive activity of DUSP6 is also interpreted by recent reports that include the downregulation of DUSP6 in leukemic cells, involvement in induction of apoptosis by chemotherapy in leukemic cells, suppressive roles in experimental skin carcinogenesis, and involvement in the growth suppression of Jurkat T cells.(56–59) The abrogation of expression of DUSP6 is confined in invasive carcinoma, whereas aberrations of other major suppressive molecules are observed in PanINs.(30) This final finding suggests that DUSP6 functions as a gatekeeper from PanIN to invasive carcinoma, which is independent of other major tumor suppressors (Fig. 3).

image

Figure 2. The RAS-MAPK pathway with abrogation of DUSP6. Active RAS generated by mutated KRAS activates downstream cascades including RAF1-MAP2K1-MAPK1. Loss of expression of DUSP6 results in abrogation of the feedback loop between MAPK1 and DUSP6 and leads to constitutive activation of MAPK1, which eventually results in invasive phenotypes.

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image

Figure 3. Molecular pathways of pancreatic carcinogenesis. Activation of KRAS and SHH along with inactivation of CDKN2A contribute to the formation of low-grade pancreatic intraepithelial neoplasia (PanIN). Additional inactivation of TP53 and SMAD4 contributes to one step up the carcinogenesis stairs; the tumors turn into high-grade PanIN. Finally, inactivation of DUSP6 leads to pancreatic ductal adenocarcinoma. PDA, pancreatic ductal adenocarcinoma.

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Because the precise localization of DUSP6, the candidate TSG in 12q, is outside of SRO in this region,(51) MMCT-mediated introduction of chromosome 12 was performed, and it was found that the hybrid cells showed growth suppression in vivo through angiogenesis inhibition.(60) Microarray analysis revealed that expression of DUSP6 remained at the suppressed level even in hybrid cells.(60) Therefore, a TSG(s) beside DUSP6 is hidden in 12q that should be unveiled in future investigations.

Conclusion

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

PDAs harbor complicated combinations of aberrations of alleles. These aberrations are distinctive in pancreatic ductal adenocarcinoma and are useful as diagnostic markers. The promotion of pancreatic carcinogenesis is obviously initiated by mutation of KRAS and aberrant expression of SHH. Overexpression of AURKA mapping on 20q13.2 may significantly enhance overt tumorigenesity. Aberrations of tumor suppressor genes synergistically accelerate the progression of carcinogenesis through PanIN to PDA. Abrogation of CDKN2A occurs in low-grade/early PanIN, whereas aberrations of TP53 occur in high-grade/late PanIN; they may play different roles in the progression of carcinogenesis. SMAD4 may play a suppressive role in tumorigenesis by inhibiting angiogenesis. Restoration of chromosome 18 in pancreatic cancer cells results in tumor suppressive phenotypes regardless of SMAD4 status, which suggests the possible existence of a yet-to-be discovered TSG(s) in addition to SMAD4. DUSP6 at 12q21-q22 is frequently abrogated by loss of expression in invasive ductal adenocarcinomas despite fairly preserved expression in PanINs, which suggests that DUSP6 is a tumor suppressor functioning as a gatekeeper of pancreatic carcinogenesis. Restoration of chromosome 12 in pancreatic cancer cells has revealed tumor suppressive phenotypes in vivo without recovery of DUSP6 expression; a buried TSG(s) in 12q is awaiting our discovery. At present, the major pancreatic carcinogenic pathway can be modeled by involving these key molecules (Fig. 3). There is a possibility of innovation for accurate and effective diagnosis using the cells obtained from the pancreatic juice and the molecules in this schema. For this purpose, we must improve this schema by adding more molecules. The understanding of the molecular mechanisms of pancreatic carcinogenesis will likely provide novel clues for preventing, detecting and ultimately curing patients with this life-threatening disease.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References

We are grateful to all the members of the pancreatic cancer research group in our laboratory, the surgeons and physicians led by Drs Seiki Matsuno and Tooru Shimosegawa, respectively, at Tohoku University Hospital, and all the collaborators for continuing fruitful collaborations for many years. We are also grateful to Dr Barbara Lee Smith Pierce (Professor, University of Maryland University College) for editorial work in the preparation of this manuscript. This work was supported by the Ministries of Education, Culture, Sports, Science and Technology of Japan, Health, Labor and Welfare of Japan, and many non-profit foundations.

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  1. Top of page
  2. Abstract
  3. Genomic analysis of pancreatic cancer
  4. Promoting molecules
  5. Aberrations of suppressive pathways
  6. Familial pancreatic cancer
  7. Impact of loss of chromosome 18q
  8. Tumor suppressor on chromosome 12q
  9. Conclusion
  10. Acknowledgments
  11. References
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