Pancreatic cancer pathophysiology: Difference between revisions

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*'''p53'''<ref name="pmid9646028">{{cite journal |vauthors=Li Y, Bhuiyan M, Vaitkevicius VK, Sarkar FH |title=Molecular analysis of the p53 gene in pancreatic adenocarcinoma |journal=Diagn. Mol. Pathol. |volume=7 |issue=1 |pages=4–9 |year=1998 |pmid=9646028 |doi= |url=}}</ref>  
*'''p53'''<ref name="pmid9646028">{{cite journal |vauthors=Li Y, Bhuiyan M, Vaitkevicius VK, Sarkar FH |title=Molecular analysis of the p53 gene in pancreatic adenocarcinoma |journal=Diagn. Mol. Pathol. |volume=7 |issue=1 |pages=4–9 |year=1998 |pmid=9646028 |doi= |url=}}</ref>  
** Deletion or mutation of [[P53 (protein)|p53]] causes its inactivation in at least half of the [[Pancreatic cancer|pancreatic cancers]]. [[P53 (protein)|p53]] is a [[tumor suppressor gene]] that is involved in [[cell cycle]] control and induction of [[apoptosis]].
** Deletion or [[mutation]] of [[P53 (protein)|p53]] causes its inactivation in at least half of the [[Pancreatic cancer|pancreatic cancers]]. [[P53 (protein)|p53]] is a [[tumor suppressor gene]] that is involved in [[cell cycle]] control and induction of [[apoptosis]].
** [[P53 (protein)|p53]] stimulates the production of p21WAF1, which inhibits the complex of [[cyclin D1]] and [[Cyclin-dependent kinase 2|CDK2]], causing cell cycle arrest at the [[G1 phase]] and inhibition of [[cell growth]].  
** [[P53 (protein)|p53]] stimulates the production of p21WAF1, which inhibits the complex of [[cyclin D1]] and [[Cyclin-dependent kinase 2|CDK2]], causing cell cycle arrest at the [[G1 phase]] and inhibition of [[cell growth]].  
** [[P53 (protein)|p53]] inactivation causes uncontrolled [[cell growth]] and proliferation.
** [[P53 (protein)|p53]] inactivation causes uncontrolled [[cell growth]] and proliferation.
** The established association of Kras mutations with [[P53 (protein)|p53]] inactivation is suggestive of crosstalk between different [[Cell signaling|signaling pathways]] involved in [[Pancreas|pancreatic]] [[carcinogenesis]].  
** The established association of [[KRAS|Kras mutations]] with [[P53 (protein)|p53]] inactivation is suggestive of crosstalk between different [[Cell signaling|signaling pathways]] involved in [[Pancreas|pancreatic]] [[carcinogenesis]].  
** Loss of [[P53 (protein)|p53]] can also determine a patient’s response to [[chemotherapy]] as its inactivation can increase resistance to certain agents of [[chemotherapy]].
** Loss of [[P53 (protein)|p53]] can also determine a patient’s response to [[chemotherapy]] as its inactivation can increase resistance to certain agents of [[chemotherapy]].
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** DPC4 has been found to be deleted in approximately half of all [[Pancreatic cancer|pancreatic cancers]].  
** DPC4 has been found to be deleted in approximately half of all [[Pancreatic cancer|pancreatic cancers]].  
** The inactivation of DPC4 causes impaired function of a [[gene]] that plays an important role in the inhibition of [[cell growth]] and [[angiogenesis]].  
** The inactivation of DPC4 causes impaired function of a [[gene]] that plays an important role in the inhibition of [[cell growth]] and [[angiogenesis]].  
** DPC4 inactivation causes increased [[angiogenesis]] and proliferation of [[Cancer|cancer cells]], with increase in the incidence of poorly differentiated [[Tumor|tumors]], thereby worsening [[prognosis]] in patients.
** DPC4 inactivation causes increased [[angiogenesis]] and proliferation of [[Cancer|cancer cells]], with increase in the [[incidence]] of poorly differentiated [[Tumor|tumors]], thereby worsening [[prognosis]] in patients.
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*  '''BRCA2'''<ref name="pmid11561603" /><ref name="pmid8968085">{{cite journal |vauthors=Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE |title=Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas |journal=Cancer Res. |volume=56 |issue=23 |pages=5360–4 |year=1996 |pmid=8968085 |doi= |url=}}</ref><ref name="pmid12569143">{{cite journal |vauthors=Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, Gerdes B, Kress R, Ziegler A, Raeburn JA, Campra D, Grützmann R, Rehder H, Rothmund M, Schmiegel W, Neoptolemos JP, Bartsch DK |title=BRCA2 germline mutations in familial pancreatic carcinoma |journal=J. Natl. Cancer Inst. |volume=95 |issue=3 |pages=214–21 |year=2003 |pmid=12569143 |doi= |url=}}</ref><ref name="pmid12097290">{{cite journal |vauthors=Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, Hruban RH, Kern SE |title=Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17% |journal=Cancer Res. |volume=62 |issue=13 |pages=3789–93 |year=2002 |pmid=12097290 |doi= |url=}}</ref><ref name="pmid9443984">{{cite journal |vauthors=Hruban RH, Petersen GM, Ha PK, Kern SE |title=Genetics of pancreatic cancer. From genes to families |journal=Surg. Oncol. Clin. N. Am. |volume=7 |issue=1 |pages=1–23 |year=1998 |pmid=9443984 |doi= |url=}}</ref>   
*  '''BRCA2'''<ref name="pmid11561603" /><ref name="pmid8968085">{{cite journal |vauthors=Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE |title=Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas |journal=Cancer Res. |volume=56 |issue=23 |pages=5360–4 |year=1996 |pmid=8968085 |doi= |url=}}</ref><ref name="pmid12569143">{{cite journal |vauthors=Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, Gerdes B, Kress R, Ziegler A, Raeburn JA, Campra D, Grützmann R, Rehder H, Rothmund M, Schmiegel W, Neoptolemos JP, Bartsch DK |title=BRCA2 germline mutations in familial pancreatic carcinoma |journal=J. Natl. Cancer Inst. |volume=95 |issue=3 |pages=214–21 |year=2003 |pmid=12569143 |doi= |url=}}</ref><ref name="pmid12097290">{{cite journal |vauthors=Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, Hruban RH, Kern SE |title=Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17% |journal=Cancer Res. |volume=62 |issue=13 |pages=3789–93 |year=2002 |pmid=12097290 |doi= |url=}}</ref><ref name="pmid9443984">{{cite journal |vauthors=Hruban RH, Petersen GM, Ha PK, Kern SE |title=Genetics of pancreatic cancer. From genes to families |journal=Surg. Oncol. Clin. N. Am. |volume=7 |issue=1 |pages=1–23 |year=1998 |pmid=9443984 |doi= |url=}}</ref>   
**  [[BRCA2]], a [[gene]] that participates in [[DNA repair|DNA damage repair]] has also been implicated in the [[pathogenesis]] of [[pancreatic cancer]] by altering the [[G1/S transition|G1 to S cell cycle transition.]]
**  [[BRCA2]], a [[gene]] that participates in [[DNA repair|DNA damage repair]] has also been implicated in the [[pathogenesis]] of [[pancreatic cancer]] by altering the [[G1/S transition|G1 to S cell cycle transition.]]
'''Activation of oncogenes:'''  
'''Activation of oncogenes:'''  
* Oncogenes may be activated by:  
* [[Oncogenes]] may be activated by:  
** [[Amplification]]  
** [[Amplification]]  
** [[Point mutation]]  
** [[Point mutation]]  
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** Rearrangement  
** Rearrangement  
** [[Mutation]]  
** [[Mutation]]  
* [[EGFR]] consists of an intracellular [[tyrosine kinase]] domain and its activation causes mobilization of molecules in different [[Cell signaling|cell signaling pathways]] by transphosphorylation of [[tyrosine]] residues.  
* [[EGFR]] consists of an [[intracellular]] [[tyrosine kinase]] domain and its activation causes mobilization of molecules in different [[Cell signaling|cell signaling pathways]] by transphosphorylation of [[tyrosine]] residues.  
*  Alterations of [[EGFR]] stimulate receptor [[Tyrosine kinase|tyrosine kinases]] and promote the development and progression of [[pancreatic cancer]] by influencing:<ref name="pmid16909423">{{cite journal |vauthors=Marshall J |title=Clinical implications of the mechanism of epidermal growth factor receptor inhibitors |journal=Cancer |volume=107 |issue=6 |pages=1207–18 |year=2006 |pmid=16909423 |doi=10.1002/cncr.22133 |url=}}</ref><ref name="pmid16885366">{{cite journal |vauthors=Wang Z, Sengupta R, Banerjee S, Li Y, Zhang Y, Rahman KM, Aboukameel A, Mohammad R, Majumdar AP, Abbruzzese JL, Sarkar FH |title=Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer |journal=Cancer Res. |volume=66 |issue=15 |pages=7653–60 |year=2006 |pmid=16885366 |doi=10.1158/0008-5472.CAN-06-1019 |url=}}</ref><ref name="pmid16424038">{{cite journal |vauthors=Zhang Y, Banerjee S, Wang Z, Xu H, Zhang L, Mohammad R, Aboukameel A, Adsay NV, Che M, Abbruzzese JL, Majumdar AP, Sarkar FH |title=Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer |journal=Cancer Res. |volume=66 |issue=2 |pages=1025–32 |year=2006 |pmid=16424038 |doi=10.1158/0008-5472.CAN-05-2968 |url=}}</ref><ref name="pmid15867387">{{cite journal |vauthors=Zhang Y, Banerjee S, Wang ZW, Marciniak DJ, Majumdar AP, Sarkar FH |title=Epidermal growth factor receptor-related protein inhibits cell growth and induces apoptosis of BxPC3 pancreatic cancer cells |journal=Cancer Res. |volume=65 |issue=9 |pages=3877–82 |year=2005 |pmid=15867387 |doi=10.1158/0008-5472.CAN-04-3654 |url=}}</ref>
*  Alterations of [[EGFR]] stimulate receptor [[Tyrosine kinase|tyrosine kinases]] and promote the development and progression of [[pancreatic cancer]] by influencing:<ref name="pmid16909423">{{cite journal |vauthors=Marshall J |title=Clinical implications of the mechanism of epidermal growth factor receptor inhibitors |journal=Cancer |volume=107 |issue=6 |pages=1207–18 |year=2006 |pmid=16909423 |doi=10.1002/cncr.22133 |url=}}</ref><ref name="pmid16885366">{{cite journal |vauthors=Wang Z, Sengupta R, Banerjee S, Li Y, Zhang Y, Rahman KM, Aboukameel A, Mohammad R, Majumdar AP, Abbruzzese JL, Sarkar FH |title=Epidermal growth factor receptor-related protein inhibits cell growth and invasion in pancreatic cancer |journal=Cancer Res. |volume=66 |issue=15 |pages=7653–60 |year=2006 |pmid=16885366 |doi=10.1158/0008-5472.CAN-06-1019 |url=}}</ref><ref name="pmid16424038">{{cite journal |vauthors=Zhang Y, Banerjee S, Wang Z, Xu H, Zhang L, Mohammad R, Aboukameel A, Adsay NV, Che M, Abbruzzese JL, Majumdar AP, Sarkar FH |title=Antitumor activity of epidermal growth factor receptor-related protein is mediated by inactivation of ErbB receptors and nuclear factor-kappaB in pancreatic cancer |journal=Cancer Res. |volume=66 |issue=2 |pages=1025–32 |year=2006 |pmid=16424038 |doi=10.1158/0008-5472.CAN-05-2968 |url=}}</ref><ref name="pmid15867387">{{cite journal |vauthors=Zhang Y, Banerjee S, Wang ZW, Marciniak DJ, Majumdar AP, Sarkar FH |title=Epidermal growth factor receptor-related protein inhibits cell growth and induces apoptosis of BxPC3 pancreatic cancer cells |journal=Cancer Res. |volume=65 |issue=9 |pages=3877–82 |year=2005 |pmid=15867387 |doi=10.1158/0008-5472.CAN-04-3654 |url=}}</ref>
** [[Cell cycle]] progression and [[Division (biology)|division]]
** [[Cell cycle]] progression and [[Division (biology)|division]]
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* Under normal conditions, [[NF-κB]] is sequestered in the cytoplasm under tight association with its inhibitors: p100 proteins and IκB.  
* Under normal conditions, [[NF-κB]] is sequestered in the cytoplasm under tight association with its inhibitors: p100 proteins and IκB.  
* [[NF-κB]] is activated by [[phosphorylation]] of IκB and p100, resulting in the translocation of active [[NF-κB]] into the [[Cell nucleus|nucleus]], thereby up-regulating [[Transcription (genetics)|gene transcription]].  
* [[NF-κB]] is activated by [[phosphorylation]] of IκB and p100, resulting in the translocation of active [[NF-κB]] into the [[Cell nucleus|nucleus]], thereby up-regulating [[Transcription (genetics)|gene transcription]].  
* The constitutive activation of [[NF-κB]] in [[pancreatic cancer]] causes increased expression of many [[Gene|genes]] eg. uPA , survivin, [[Vascular endothelial growth factor|VEGF]], [[Matrix metalloproteinase|MMP]]-9, involved in: <ref name="pmid12767057">{{cite journal |vauthors=Liptay S, Weber CK, Ludwig L, Wagner M, Adler G, Schmid RM |title=Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer |journal=Int. J. Cancer |volume=105 |issue=6 |pages=735–46 |year=2003 |pmid=12767057 |doi=10.1002/ijc.11081 |url=}}</ref><ref name="pmid15665315">{{cite journal |vauthors=Rahman KW, Sarkar FH |title=Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3'-diindolylmethane-induced apoptosis in breast cancer cells |journal=Cancer Res. |volume=65 |issue=1 |pages=364–71 |year=2005 |pmid=15665315 |doi= |url=}}</ref><ref name="pmid12687011">{{cite journal |vauthors=Zhang H, Morisaki T, Nakahara C, Matsunaga H, Sato N, Nagumo F, Tadano J, Katano M |title=PSK-mediated NF-kappaB inhibition augments docetaxel-induced apoptosis in human pancreatic cancer cells NOR-P1 |journal=Oncogene |volume=22 |issue=14 |pages=2088–96 |year=2003 |pmid=12687011 |doi=10.1038/sj.onc.1206310 |url=}}</ref>
* The constitutive activation of [[NF-κB]] in [[pancreatic cancer]] causes increased expression of many [[Gene|genes]] eg. uPA , survivin, [[Vascular endothelial growth factor|VEGF]], [[Matrix metalloproteinase|MMP]]-9, involved in: <ref name="pmid12767057">{{cite journal |vauthors=Liptay S, Weber CK, Ludwig L, Wagner M, Adler G, Schmid RM |title=Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer |journal=Int. J. Cancer |volume=105 |issue=6 |pages=735–46 |year=2003 |pmid=12767057 |doi=10.1002/ijc.11081 |url=}}</ref><ref name="pmid15665315"><nowiki>{{cite journal |vauthors=Rahman KW, Sarkar FH |title=Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3'-diindolylmethane-induced apoptosis in breast cancer cells |journal=Cancer Res. |volume=65 |issue=1 |pages=364–71 |year=2005 |pmid=15665315 |doi= |url=}}</nowiki></ref><ref name="pmid12687011">{{cite journal |vauthors=Zhang H, Morisaki T, Nakahara C, Matsunaga H, Sato N, Nagumo F, Tadano J, Katano M |title=PSK-mediated NF-kappaB inhibition augments docetaxel-induced apoptosis in human pancreatic cancer cells NOR-P1 |journal=Oncogene |volume=22 |issue=14 |pages=2088–96 |year=2003 |pmid=12687011 |doi=10.1038/sj.onc.1206310 |url=}}</ref>
** [[Apoptosis]]  
** [[Apoptosis]]  
** [[Cell growth]]  
** [[Cell growth]]  
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* Activated [[Phosphoinositide 3-kinase|PI3K]] phosphorylates phosphatidylinositides ([[Phosphatidylinositol (3,4,5)-trisphosphate|PIP3]]) and this, in turn causes [[phosphorylation]] and activation of [[AKT|Akt]].  
* Activated [[Phosphoinositide 3-kinase|PI3K]] phosphorylates phosphatidylinositides ([[Phosphatidylinositol (3,4,5)-trisphosphate|PIP3]]) and this, in turn causes [[phosphorylation]] and activation of [[AKT|Akt]].  
*  [[Phosphorylation]] of [[AKT|Akt]] (p-Akt)  activates [[NF-κB]] and  inhibits [[apoptosis]], thereby promoting cell survival.  
*  [[Phosphorylation]] of [[AKT|Akt]] (p-Akt)  activates [[NF-κB]] and  inhibits [[apoptosis]], thereby promoting cell survival.  
* Akt also regulates the [[NF-κB]] pathway via [[phosphorylation]] and activation, causing [[upregulation]] of [[Transcription (genetics)|gene transcription]].
* [[AKT|Akt]] also regulates the [[NF-κB]] pathway via [[phosphorylation]] and activation, causing [[upregulation]] of [[Transcription (genetics)|gene transcription]].
'''Deregulation of Hedgehog signaling''':<ref name="pmid22116519" /><ref name="pmid16849549">{{cite journal |vauthors=Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, Tanaka M, Katano M |title=Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer |journal=Cancer Res. |volume=66 |issue=14 |pages=7041–9 |year=2006 |pmid=16849549 |doi=10.1158/0008-5472.CAN-05-4588 |url=}}</ref><ref name="pmid14520413">{{cite journal |vauthors=Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernández-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M |title=Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis |journal=Nature |volume=425 |issue=6960 |pages=851–6 |year=2003 |pmid=14520413 |pmc=3688051 |doi=10.1038/nature02009 |url=}}</ref><ref name="pmid14520411">{{cite journal |vauthors=Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA |title=Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours |journal=Nature |volume=425 |issue=6960 |pages=846–51 |year=2003 |pmid=14520411 |doi=10.1038/nature01972 |url=}}</ref><ref name="pmid25310976">{{cite journal |vauthors=Mathew E, Zhang Y, Holtz AM, Kane KT, Song JY, Allen BL, Pasca di Magliano M |title=Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling |journal=Cell Rep |volume=9 |issue=2 |pages=484–94 |year=2014 |pmid=25310976 |pmc=4362534 |doi=10.1016/j.celrep.2014.09.010 |url=}}</ref>  
'''Deregulation of Hedgehog signaling''':<ref name="pmid22116519" /><ref name="pmid16849549">{{cite journal |vauthors=Nakashima H, Nakamura M, Yamaguchi H, Yamanaka N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, Tanaka M, Katano M |title=Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer |journal=Cancer Res. |volume=66 |issue=14 |pages=7041–9 |year=2006 |pmid=16849549 |doi=10.1158/0008-5472.CAN-05-4588 |url=}}</ref><ref name="pmid14520413">{{cite journal |vauthors=Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernández-del Castillo C, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M |title=Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis |journal=Nature |volume=425 |issue=6960 |pages=851–6 |year=2003 |pmid=14520413 |pmc=3688051 |doi=10.1038/nature02009 |url=}}</ref><ref name="pmid14520411">{{cite journal |vauthors=Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA |title=Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours |journal=Nature |volume=425 |issue=6960 |pages=846–51 |year=2003 |pmid=14520411 |doi=10.1038/nature01972 |url=}}</ref><ref name="pmid25310976">{{cite journal |vauthors=Mathew E, Zhang Y, Holtz AM, Kane KT, Song JY, Allen BL, Pasca di Magliano M |title=Dosage-dependent regulation of pancreatic cancer growth and angiogenesis by hedgehog signaling |journal=Cell Rep |volume=9 |issue=2 |pages=484–94 |year=2014 |pmid=25310976 |pmc=4362534 |doi=10.1016/j.celrep.2014.09.010 |url=}}</ref>  
* In case of [[Pancreas|pancreatic]] development in the [[embryo]], [[Hedgehog signaling pathway|Hedgehog (Hh) signaling]] is an essential pathway.  
* In case of [[Pancreas|pancreatic]] development in the [[embryo]], [[Hedgehog signaling pathway|Hedgehog (Hh) signaling]] is an essential pathway.  
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==Gross Pathology==
==Gross Pathology==
The [[gross pathology]] of [[Pancreatic cancer|pancreatic adenocarcinoma]], which accounts for three-fourths of all [[Pancreas|pancreatic]] [[Cancer|malignancies]] is as follows:<ref name="pmid25320520">{{cite journal |vauthors=Esposito I, Konukiewitz B, Schlitter AM, Klöppel G |title=Pathology of pancreatic ductal adenocarcinoma: facts, challenges, and future developments |journal=World J. Gastroenterol. |volume=20 |issue=38 |pages=13833–41 |year=2014 |pmid=25320520 |pmc=4194566 |doi=10.3748/wjg.v20.i38.13833 |url=}}</ref>
The [[gross pathology]] of [[Pancreatic cancer|pancreatic adenocarcinoma]], which accounts for three-fourths of all [[Pancreas|pancreatic]] [[Cancer|malignancies]] is as follows:<ref name="pmid25320520">{{cite journal |vauthors=Esposito I, Konukiewitz B, Schlitter AM, Klöppel G |title=Pathology of pancreatic ductal adenocarcinoma: facts, challenges, and future developments |journal=World J. Gastroenterol. |volume=20 |issue=38 |pages=13833–41 |year=2014 |pmid=25320520 |pmc=4194566 |doi=10.3748/wjg.v20.i38.13833 |url=}}</ref>
* Grossly, ductal [[Adenocarcinoma|adenocarcinomas]] of the [[pancreas]] tend to be gritty, hard, gray-white poorly defined masses that cause obstruction of the main pancreatic duct and the distal [[common bile duct]].  
* Grossly, ductal [[Adenocarcinoma|adenocarcinomas]] of the [[pancreas]] tend to be gritty, hard, gray-white poorly defined masses that cause obstruction of the main [[pancreatic duct]] and the distal [[common bile duct]].  
* [[Chronic pancreatitis]] of the obstructed [[Pancreas|pancreatic]] segment arises due to obstruction of the main [[Pancreas|pancreatic]] [[Duct (anatomy)|duct]].
* [[Chronic pancreatitis]] of the obstructed [[Pancreas|pancreatic]] segment arises due to obstruction of the main [[Pancreas|pancreatic]] [[Duct (anatomy)|duct]].
* Patients do not present with [[malabsorption]] or [[steatorrhea]] as the accessory duct of Santorini can still allow bypass of the main [[pancreatic duct]].
* Patients do not present with [[malabsorption]] or [[steatorrhea]] as the accessory [[duct of Santorini]] can still allow bypass of the main [[pancreatic duct]].
* The [[Head of pancreas|head of the pancreas]] is most commonly involved.
* The [[Head of pancreas|head of the pancreas]] is most commonly involved.
* [[Head of pancreas|Head lesions]] make up 75% of all lesions, while the rest are body/tail [[Lesion|lesions]].
* [[Head of pancreas|Head lesions]] make up 75% of all lesions, while the rest are body/tail [[Lesion|lesions]].
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[[Category:Gastroenterology]]
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Surgery]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]

Latest revision as of 13:53, 14 March 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]

Overview

The development of pancreatic cancer is influenced by complex interactions between several cellular signaling pathways that include inactivation of tumor suppressor genes, activation of oncogenes and deregulation of molecules in various signaling pathways. Some of the important tumor suppressor genes involved are p53, p16, p27CIP1, DPC4 and BRCA2. These tumor suppressor genes are commonly inactivated by deletion, hypermethylation or mutation. The oncogenes involved in the pathogenesis of pancreatic cancer include Ras, Cox-2, Akt-2, Notch, Cyclin- D1 genes. Signal transduction pathways such as EGFR, Akt, NF-kB and Hedgehog pathways undergo genomic alterations and crosstalk between these pathways plays an important role in pancreatic tumorigenesis.

Pathophysiology

Pathogenesis and Genetics

Inactivation of tumor suppressor genes:






Activation of oncogenes:






Deregulation of EGFR signalling:[50]


Deregulation of NF-κB signalling: [55][56][57][58][59][60][61][62]


Deregulation of Akt signaling:

Deregulation of Hedgehog signaling:[12][66][67][68][69]

Gross Pathology

The gross pathology of pancreatic adenocarcinoma, which accounts for three-fourths of all pancreatic malignancies is as follows:[70]

Microscopic Pathology

On microscopic histopathological analysis, the following features are noted:[71]

  • Microscopic study reveals the following:
  • Other features:

References

  1. ↑ 1.0 1.1 Cowgill SM, Muscarella P (2003). "The genetics of pancreatic cancer". Am. J. Surg. 186 (3): 279–86. PMID 12946833.
  2. ↑ Hruban RH, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ, Falatko F, Yeo CJ, Kern SE (1999). "Familial pancreatic cancer". Ann. Oncol. 10 Suppl 4: 69–73. PMID 10436789.
  3. ↑ Greer JB, Whitcomb DC, Brand RE (2007). "Genetic predisposition to pancreatic cancer: a brief review". Am. J. Gastroenterol. 102 (11): 2564–9. doi:10.1111/j.1572-0241.2007.01475.x. PMID 17958761.
  4. ↑ Soto JL, Barbera VM, Saceda M, Carrato A (2006). "Molecular biology of exocrine pancreatic cancer". Clin Transl Oncol. 8 (5): 306–12. PMID 16760004.
  5. ↑ Shi C, Daniels JA, Hruban RH (2008). "Molecular characterization of pancreatic neoplasms". Adv Anat Pathol. 15 (4): 185–95. doi:10.1097/PAP.0b013e31817bf57d. PMID 18580095.
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