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  • Review Article
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Pancreatic cancer biology and genetics

Nature Reviews Cancer volume 2, pages 897–909 (2002)Cite this article

Key Points

  • Pancreatic adenocarcinoma is a highly aggressive malignancy that shows profound resistance to extant treatments.

  • Genetic studies identified a signature molecular profile of this malignancy, consisting of mutations in KRAS, CDKN2A, TP53 and SMAD4/DPC4.

  • Pancreatic adenocarcinomas seem to arise from the progression of lesions that occur in the pancreatic ducts (pancreatic intraepithelial neoplasia, PanIN). Although the mutations listed above seem to occur in a temporal sequence in progressive PanIN stages, the specific biochemical and cellular events resulting from the mutations are not known.

  • This tumour type shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in TP53 and BRCA2 are likely to contribute to these phenotypes.

  • There is ongoing study of the cell of origin in pancreatic adenocarcinoma. Although there is general agreement that the pancreatic ductal epithelial cell gives rise to this malignancy, there is evidence that transdifferentiation of other pancreatic cell types, such as acinar cells, might serve as an alternative route to pancreatic adenocarcinoma.

  • These tumours show an extensive proliferation of stromal fibroblasts and deposition of extracellular-matrix components (desmoplasia) that seem to promote growth and invasiveness. The molecular basis of this phenotype is not resolved, although TGF-β is thought to have a role.

  • Engineered mouse models have recapitulated some of the genetic and histological features of the human disease. The use of refined methodologies, such as tissue-specific mouse knockouts, should give insight into the biological and biochemical impact of tumour-suppressor gene loss or oncogene activation in pancreatic neoplasia.

Abstract

Pancreatic ductal adenocarcinoma is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression and profound resistance to treatment. Advances in pathological classification and cancer genetics have improved our descriptive understanding of this disease; however, important aspects of pancreatic cancer biology remain poorly understood. What is the pathogenic role of specific gene mutations? What is the cell of origin? And how does the stroma contribute to tumorigenesis? A better understanding of pancreatic cancer biology should lead the way to more effective treatments.

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Figure 1: Anatomy of the pancreas.
Figure 2: Genetic progression model of pancreatic adenocarcinoma.
Figure 3: Telomere attrition and genomic instability.
Figure 4: Model of relationship of pancreatic regeneration and tumorigenesis.

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Authors and Affiliations

  1. Department of Adult Oncology, Dana–Farber Cancer Institute and Departments of Medicine and Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Nabeel Bardeesy & Ronald A. DePinho

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  1. Nabeel Bardeesy
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  2. Ronald A. DePinho
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Correspondence to Ronald A. DePinho.

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DATABASES

Cancer.gov

pancreatic adenocarcinoma

LocusLink

BRCA2

CDK4

CDK6

CDKN2A

EGF

EGFR

ERBB2

ERBB3

KRAS

LKB1

MDM2

MLH1

MSH2

MSH6

Pdx1

PRSS1

RB

SMAD4

TGF-α

TP53

WAF1

OMIM

FAMMM syndrome

hereditary pancreatitis

HNPCC syndrome

Peutz–Jeghers syndrome

FURTHER INFORMATION

Pancreatic Cancer Agenda for Action

Glossary

PANCREATIC ADENOCARCINOMA

The most common type of cancer of the pancreas, accounting for greater than 85% of pancreatic neoplasms. These tumours show histological resemblance to the pancreatic ducts and are also referred to as pancreatic ductal adenocarcinoma, or simply pancreatic cancer.

PANCREATICODUODENECTOMY

A surgical resection of the distal stomach, duodenum, common duct, and head of the pancreas, containing the pancreatic neoplasm.

INK4A

A cyclin-dependent kinase inhibitor that acts on cyclin-D–CDK4/6. It prevents hyperphosphorylation and inactivation of RB, so cells can not enter S phase.

ARF

A regulator of p53 that functions by inhibiting MDM2-dependent proteolysis of p53.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

MAPK PATHWAY

A signal-transduction pathway that is crucial for the integration of mitogenic signals mediated by various growth factors. Activation of this pathway is involved in many cellular processes, including cell-cycle progression.

AUTOCRINE SIGNALLING

A signal-transduction mechanism in which both a secreted ligand and corresponding cell-surface receptor are expressed by the same cell.

PI3K PATHWAY

The phosphatidylinositol 3-kinase (PI3K) family of enzymes are activated in response to various stimuli and catalyse the phophorylation of inositol lipids at the d-3 position of the inositol ring. These phosphoinositides act as second messengers; a primary target is the serine/threonine kinase AKT (protein kinase B). Activated AKT phosphorylates several cellular targets, including proteins that are involved in cell survival, proliferation and migration.

FIELD DEFECT

The independent transformation of different epithelial cells following exposure of an area of tissue to carcinogenic insults.

COMPARATIVE GENOMIC HYBRIDIZATION

A method that is used to detect chromosome copy-number alterations. Tumour and control DNA are labelled with different coloured fluorescent dyes and hybridized to metaphase chromosomes. Deletions/amplifications are visualized by changes in the fluorescent spectrum at specific chromosomal regions. Array-CGH allows higher resolution and accuracy as it uses hybridization to small DNA fragments that are arranged on microchips.

TRANSFORMING GROWTH FACTOR-β FAMILY

Secreted growth factors, comprising the TGF-β, bone morphogenic protein and activin families, which transduce signals through specific cell-surface receptors. These signalling pathways control many morphogenic and homeostatic processes. SMAD4 mediates TGF-β-family signalling, linking receptor stimulation to transcriptional responses by complexing with specific receptor-activated SMADs and other transcriptional components.

STROMA

The non-transformed component of epithelial tumours, comprised of fibroblasts, blood-vessel elements and immune cells. The stromal cells do not show the same clonal genetic changes as the malignant tumour cells, yet are altered by molecular events in the tumour cells and, in turn, modulate biological features of the tumour compartment. These heterotypic interactions are fundamental to tumour genesis and progression.

CELL OF ORIGIN

The cell type and specific developmental stage from which a tumour type evolves. Although epithelial tumours are classified by their histological resemblance to normal cellular counterparts, this might not strictly indicate a cell-lineage relationship, given the known developmental plasticity of malignant cells. Understanding the cell of origin in pancreatic adenocarcinoma might help in prevention, diagnosis and treatment.

TRANSDIFFERENTIATION

The conversion of one differentiated cell type into another. Transdifferentiation and the conversion between undifferentiated stem cells of different tissue are subclasses of metaplasia.

APC Min/+

A mouse strain that is prone to the development of multiple intestinal polyps, due to mutations in the Apc gene — the homologue of the human familial colon cancer gene.

CRE RECOMBINASE

An enzyme that is derived from the P1 bacteriophage that binds to a 34-base-pair DNA sequence (loxP site). Sequences flanked by loxP sites can be excised by Cre recombinase expression. The Cre–Lox system is a technology that allows genes to be ablated in a tissue-selective and inducible manner.

AVIAN RETROVIRAL RECEPTOR

An avian cell-surface protein that is required for infection by the avian sarcoma and leukosis virus (ASLV). Tissue-specific expression of the gene encoding this receptor in transgenic mice enables infection of these tissues with ASLV, allowing somatically targeted gene transfer.

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Bardeesy, N., DePinho, R. Pancreatic cancer biology and genetics. Nat Rev Cancer 2, 897–909 (2002). https://doi.org/10.1038/nrc949

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