Pancreatic cancer pathophysiology

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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

Pancreatic cancer is the result of activation or inactivation of multiple gene subsets. The progression and development of pancreatic cancer is influenced by complex interactions and crosstalk between several cellular signaling pathways that include inactivation of tumor suppressor genes, activation of oncogenes and deregulation of molecules in various signaling pathways. EGFR, Akt, NF-kB and Hedgehog pathways are most commonly involved in the pathogenesis of pancreatic cancer. Majority of ductal adenocarcinomas have varying degrees of mucin production and duct-like structures and present as moderate-poorly differentiated masses.  The ductal adenocarcinomas are referred to as “desmoplastic” or "scirrhous" carcinomas due to their characteristic dense stromal fibrosis occurring due to alterations in transforming growth factor-beta (TGF-beta) signaling. Local extension of tumor cells may occur into adjacent structures such as superior mesenteric vessels, perineural invasion both inside and outside the pancreas (eg, the retroperitoneum), duodenum, portal vein and stomach. Lymph node spread can occur to the regional peripancreatic, mesenteric, perigastric, portahepatic and omental lymph nodes.

Pathophysiology

Pathogenesis and Genetics

Inactivation of tumor suppressor genes:



  • p16 [20][21][22][1][23][24][25][26]
    • p16 participates in the aggressiveness of pancreatic cancer by inhibiting cyclin D and CDK4/6 mediated phosphorylation of Rb in the G1/S transition of the cell cycle.
    • Phosphorylation of Rb activates genes in the cell cycle required for DNA synthesis and lack of phosphorylation inhibits cell growth.
    •  95% of the patients with pancreatic cancer have inactivated p16 with:
      • 40% deletion
      • 15% hypermethylation
      •  40% mutation
    • P16 mutation causes increased Rb phosphorylation, leading to uncontrolled cellular proliferation and increased carcinogenesis. Survival time is lesser and tumor is larger in size in patients with p16 mutation.


  • p27CIP1
    •  p27CIP1 mutations have been implicated in pancreatic cancer by altering cellular progression in the G1 to S phase.


  • DPC4
    • DPC4 has been found to be deleted in approximately half of all 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.
    • DPC4 inactivation causes increased angiogenesis and proliferation of cancer cells, with increase in the incidence of poorly differentiated tumors, thereby worsening prognosis in patients.


  •  BRCA2[23][27][28][29][30]
    •  BRCA2, a gene that participates in DNA damage repair has also been implicated in the pathogenesis of pancreatic cancer by altering the G1 to S cell cycle transition.

Activation of oncogenes:

  • Oncogenes may be activated by:
    • Amplification
    • Point mutation
  • Ras oncogene[31][32][33][34][35][36]
    • Ras oncogene activation is found in over ninety percent of pancreatic cancers. This oncogene is involved in mediating cell proliferation, migration and signal transduction.
    • Point mutation or amplification of  K-ras in the early phase of carcinogenesis leads to the formation of a constitutively activated Ras that binds to GTP and propagates uncontrolled cellular replication via downstream signalling pathways.


  • Cox-2 activation[37][38][39][40][41]
    • COX-2 is an inducible isoform of the COX enzyme and its synthesis is stimulated in pancreatic carcinogenic and inflammatory processes.
    • Activated Ras present in ninety percent of pancreatic cancers increases COX-2 mRNA stability, hence contributing to pancreatic carcinogenesis.


  • Akt-2 gene amplification
    • Akt-2 gene amplification occurs in 10–15% of pancreatic cancers leading to its activation.
    •  Activation of Akt-2 gene stimulates cell growth, thereby accelerating progression to pancreatic cancer.


  • Notch gene[42][43][44][45][46][47]
    • Notch protein activation causes translocation of Notch into the nucleus. The Notch protein is bound to transcriptional factors and plays a vital role in the development of organs and pancreatic carcinogenesis by regulating the expression of target genes.
    • Notch also contributes to pancreatic cancer by inhibition of apoptosis of cells.


  • Up-regulation of cyclin D1
    • Cyclin D1 overexpression promotes tumor cell growth and confers resistance to cisplatin, proving the effect of cyclin D1 on the pathogenesis of pancreatic cancer.[48][49]


Deregulation of EGFR signalling:[50]

  • Genomic alterations of EGFR include the following:
    • Deletion
    • Over-expression
    • Rearrangement
    • Mutation
  • EGFR consists of an intracellular tyrosine kinase domain and its activation causes mobilization of molecules in different cell signaling pathways by transphosphorylation of tyrosine residues.
  •  Alterations of EGFR stimulate receptor tyrosine kinases and promote the development and progression of pancreatic cancer by influencing:[51][52][53][54]
    • Cell cycle progression and division
    • Apoptosis
    • Angiogenesis
    • Motility
    • Invasion
    • Resistance to chemotherapy
    • Metastasis


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

  • 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 nucleus, thereby up-regulating gene transcription.
  • The constitutive activation of NF-κB in pancreatic cancer causes increased expression of many genes eg. uPA , survivin, VEGF, MMP-9, involved in: [63][64][65]
    • Apoptosis
    • Cell growth
    • Inflammation
    • Stress response
    • Cell differentiation
    • Angiogenesis
    • Invasion
    • Cell survival
    • Metastasis
    •  Pancreatic cancer cells display over expression of urokinase-type plasminogen activator (uPA), directly involved in the regulation of angiogenesis, tumor invasion and metastasis.


Deregulation of Akt signaling:

  • Deregulation of Akt signaling is found in about seventy percent of the cases of pancreatic cancer and is associated with high tumor grade and prognosis.
  • EGF binding leads to PI3K pathway activation.
  • Activated PI3K phosphorylates phosphatidylinositides (PIP3) and this, in turn causes phosphorylation and activation of Akt.
  •  Phosphorylation of 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 gene transcription.

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

  • In case of pancreatic development in the embryo, Hedgehog (Hh) signaling is an essential pathway.
  • Hedgehog signaling plays an essential role in:
    •  Tissue morphogenesis
    • Organ formation of developing gastrointestinal tract
  • Deregulation of the Hh pathway leading to overexpression of Shh is known to contribute to pancreatic tumorigenesis.
  • Sonic hedgehog signalling is aberrantly expressed in seventy percent of  pancreas specimens from carcinoma patients, implicating its role in pancreatic tumorigenesis.

Gross Pathology

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

  • Grossly, ductal 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 pancreatic segment arises due to obstruction 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 the pancreas is most commonly involved.
  • Head lesions make up 75% of all lesions, while the rest are body/tail lesions.
  • Ductal adenocarcinomas do not always originate in the main pancreatic or major branch ducts and may arise in small ducts within the peripheral acinar tissue. Hence, the term "ductal" is based on histology and not the origin.

Microscopic Pathology

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

  • Majority of ductal adenocarcinomas have varying degrees of mucin production and duct-like structures and present as moderate-poorly differentiated masses.
  •  The ductal adenocarcinomas are referred to as “desmoplastic” or "scirrhous" carcinomas due to their characteristic dense stromal fibrosis occurring due to alterations in transforming growth factor-beta (TGF-beta) signaling.
  • There is typically considerable desmoplasia or formation of a dense fibrous stroma or structural tissue consisting of a range of cell types (including myofibroblasts, macrophages, lymphocytes and mast cells) and deposited material (such as type I collagen and hyaluronic acid).
  • Local extension of tumor cells may occur into adjacent structures such as:[72]
    • Superior mesenteric vessels
    • Perineural invasion: both inside and outside the pancreas (eg, the retroperitoneum)
    • Duodenum
    • Portal vein
    • Stomach
    • Vertebral column
    • Adrenal glands
    • Spleen
    • Transverse colon
  • Lymph node spread can occur to the following sites:[73][74]
    • Regional peripancreatic lymph nodes
    • Mesenteric
    • Perigastric
    •  Portahepatic
    • Omental

References

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