Elsevier

Acta Histochemica

Volume 118, Issue 3, April 2016, Pages 305-316
Acta Histochemica

Review
Cellular and molecular aspects of pancreatic cancer

https://doi.org/10.1016/j.acthis.2016.01.009Get rights and content

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that affects nearly 50,000 patients each year. The overall 5-year survival rate for this malignancy remains the lowest of any cancer at around 7% due to limited diagnostic methods, disease aggressiveness and a lack of targeted therapeutic interventions. This review highlights the successes achieved over the past several decades as well as the significant cellular and molecular hurdles that remain in combatting this deadly disease at a translational level.

Section snippets

History

It was believed for a long time that cancer of the pancreas was not existent, and it was not until 1882 when a solid tumor was successfully excised for the first time from this tissue. The patient, however, died within hours of being discharged (Busnardo et al., 1983). Since then, many surgical procedures have been proposed for resection of malignant pancreatic tissue. Walter Kausch and Allan Whipple started performing pancreatic surgery around 1910 and developed a method known as

Factors contributing to poor survival

There are several reasons why PDAC patients have such low survival. First, there are few viable methods for detecting this malignancy early. Second, PDAC is a highly aggressive cancer and can metastasize early. Finally, few targeted therapies exist for treating PDAC, and those therapies that are used remain relatively ineffective.

Genetically engineered mouse models (GEMMs)

Genetically engineered mouse models (GEMMs) for PDAC research were created to recapitulate both genetic and morphologic alterations that often lead to the development of the disease. Experiments conducted in mouse models have shown identical results to human PDAC. Over the past decade, pancreatic cancer GEMMs have garnered significant attention since they show promise for assisting in the development of new diagnostic and therapeutic approaches. Here, we discuss genes alterations that have been

Oncogene addiction

Cancer cells often times depend on specific oncogenes for their growth and survival. This concept is known as “oncogene addiction” (Weinstein and Joe, 2008). Targeting a single oncogene that drives tumor cell survival would be the most ideal approach for defeating malignancies; however, there has been little success with this approach. Because these tumor cells are exceedingly reliant on specific oncogenes, it has been predicted that these genes or cells carry second-site mutations prior to

Proteomics

Over the past decade, proteomics has quickly found its place as a useful technique for identifying potential biomarkers or therapeutic targets since this method can detect the protein and post-translationally modified protein levels (Anderson and Anderson, 1998). Identification of such biomolecules may help in predict disease prognosis and identification of new targets; thus, in the case of PDAC, proteomics is very practical. One application of this method is to compare normal and tumor tissue

Concluding remarks

Research on pancreatic cancer has vastly increased over the past few decades, yet the survival rate has remained rather low. Advancements in technologies have provided us a “blue-print” of PDAC initiation, development and progression. This has given us the opportunity to identify potential biomarkers and therapeutic targets for this malignancy; however, more studies are required for definitive treatment options. Due to the lack of noticeable symptoms while the tumor is localized to the

Acknowledgements

We thank the members of the Kelber Lab at California State University Northridge. Funding that supported this and related work came from the CSUN College of Science and Math, Medtronic/Minimed, CSUPERB and the Sidney Stern Memorial Trust.

References (106)

  • S.R. Hingorani et al.

    Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse

    Cancer Cell

    (2003)
  • S.R. Hingorani et al.

    Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice

    Cancer Cell

    (2005)
  • S. Hishinuma et al.

    Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings

    J. Gastrointest. Surg.

    (2006)
  • S. Keller et al.

    Exosomes: from biogenesis and secretion to biological function

    Immunol. Lett.

    (2006)
  • E. Lonardo et al.

    Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy

    Cell Stem Cell

    (2011)
  • M.P. Lutz et al.

    Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma

    Biochem. Biophys. Res. Commun.

    (1998)
  • N. Milosevic et al.

    Synthetic lethality screen identifies RPS6KA2 as modifier of epidermal growth factor receptor activity in pancreatic cancer

    Neoplasia

    (2013)
  • C. Navas et al.

    EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma

    Cancer Cell

    (2012)
  • B. Ozdemir et al.

    Depletion of carcinoma-associated fibroblasts and fibrosis induces immunsuppression and accelerates pancreas cancer with reduced survival

    Cancer Cell

    (2014)
  • A.D. Rhim et al.

    EMT and dissemination precede pancreatic tumor formation

    Cell

    (2012)
  • R. Roskoski

    The ErbB/HER family of protein-tyrosine kinases and cancer

    Pharmacol. Res.

    (2014)
  • R. Shen et al.

    The biological features of PanIN initiated from oncogenic KRas mutation in genetically engineered mouse models

    Cancer Lett.

    (2013)
  • A. Vincent et al.

    Pancreatic cancer

    Lancet

    (2011)
  • M. Wagner et al.

    Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice

    Gastroenterology

    (1998)
  • H. Ying et al.

    Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism

    Cell

    (2012)
  • M. Yu et al.

    Circulating tumor cells: approaches to isolation and characterization

    J. Cell Biol.

    (2011)
  • R. Aebersold et al.

    Mass spectrometry-based proteomics

    Nature

    (2003)
  • A.J. Aguirre et al.

    Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma

    Genes Dev.

    (2003)
  • W. Allard et al.

    Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases

    Clin. Cancer Res.

    (2004)
  • N. Anderson et al.

    Proteome and proteomics: new technologies, new concepts, and new words

    Electrophoresis

    (1998)
  • N. Bardeesy et al.

    Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer

    Genes Dev.

    (2006)
  • D. Besmer et al.

    Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis

    Cancer Res.

    (2011)
  • P. Bromann et al.

    The interplay between Src family kinases and receptor tyrosine kinases

    Oncogene

    (2004)
  • N.V. Chaika et al.

    MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer

    Proc. Natl. Acad. Sci. U. S. A.

    (2012)
  • N.V. Chaika et al.

    Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma

    PLoS One

    (2012)
  • P.J. Chiao et al.

    Kras Pten, NF-kappaB, and inflammation: dangerous liaisons

    Cancer Discov.

    (2011)
  • A. Chou et al.

    Clinical and molecular characterization of HER2 amplified-pancreatic cancer

    Genome Med.

    (2013)
  • M. Collins et al.

    Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

    J. Clin. Investig.

    (2012)
  • M. Collins et al.

    Metastatic pancreatic cancer is dependent on oncogenic Kras in mice

    PLoS One

    (2012)
  • R. Cowan et al.

    Genetic progression of pancreatic cancer

    Cancer J.

    (2014)
  • M. Dean et al.

    Tumour stem cells and drug resistance

    Nat. Rev. Cancer

    (2005)
  • E. Deer et al.

    Phenotype and genotype of pancreatic cancer cell lines

    Pancreas

    (2010)
  • C. Diep et al.

    Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells

    Clin. Cancer Res.

    (2011)
  • M. Erkan et al.

    Tumor microenvironment and progression of pancreatic cancer

    Exp. Oncol.

    (2010)
  • S. Eser et al.

    Oncogenic KRAS signaling in pancreatic cancer

    Br. J. Cancer

    (2014)
  • C. Feig et al.

    The pancreas cancer microenvironment

    Clin. Cancer Res.

    (2012)
  • K. Fujimura et al.

    A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer

    Cancer Res.

    (2014)
  • K.A. Goodman et al.

    Role of radiation therapy in the management of pancreatic cancer

    J. Surg. Oncol.

    (2013)
  • M. Guix et al.

    Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins

    J. Clin. Investig.

    (2008)
  • L. Hanlon et al.

    Notch1 functions as a tumor suppressor in a model of K-ras-induced pancreatic ductal adenocarcinoma

    Cancer Res.

    (2010)
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