Pancreatic cancer pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Parminder Dhingra, M.D. [2]

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Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Pathogenesis

• The pathogenesis of pancreatic cancer involves the activation or inactivation of multiple gene subsets.
• This can be categorized as follows:
  • Inactivation of tumor suppressor genes
  • Activation of oncogenes
  • Deregulation of molecules in various signalling pathways
    • EGFR
    • Akt
    • NF-kB
    • Hedgehog pathways

Inactivation of tumor suppressor genes

• Tumor suppressor genes may be inactivated by:
  •  Mutation
  • Hypermethylation
  •  Deletion
• p53
  • Deletion or mutation of p53 causes its inactivation in at least half of the pancreatic cancers. p53 is a tumor suppressor gene that is involved in cell cycle control and induction of apoptosis.
  • p53 stimulates the production of p21WAF1, which inhibits the complex of cyclin D1 and CDK2, causing cell cycle arrest at the G1 phase and inhibition of cell growth.
  • p53 inactivation causes uncontrolled cell growth and proliferation.
  • The established association of Kras mutations with p53 inactivation is suggestive of crosstalk between different signalling pathways involved in pancreatic carcinogenesis.
  • Loss of p53 can also determine a patient’s response to chemotherapy as its inactivation can increase resistance to certain agents of chemotherapy.
• p16
  • 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.

Genetics

• [Disease name] is transmitted in [mode of genetic transmission] pattern.
• Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
• The development of [disease name] is the result of multiple genetic mutations.

Associated Conditions

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

References

Overview

The pathophysiology of pancreatic adenocarcinoma includes 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).

Pathophysiology

Pathology

The most common form of pancreatic cancer (adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. 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).

References