Pathobiology of pancreatic cancer: implications on therapy

ABSTRACT

Although the concept of tumor heterogeneity was established several decades ago, the interest in this topic is still unbroken. With the identification of inter- and intratumoral genomic rearrangements and the detection of cancer stem cells (CSCs) through phenotypic variations of cancer cells there are increasing options for pancreatic cancer therapy. Indeed, some pre-clinical studies have shown promising results in the treatment of drug-resistant CSCs, whereby a few strategies were already tested in clinical trials. Basically, CSCs are influenced by the tumor microenvironment and an epigenetic reprogramming to gain stem cell-like characteristics. Targeting options inhibiting the epithelial-mesenchymal crosstalk or promoting epigenetic-driven differentiation of CSCs to a less aggressive phenotype raised the possibilities of further therapeutic applications, which will be discussed in this review.

Keywords:

• Pancreatic cancer
• tumor heterogeneity
• cancer stem cells
• tumor microenvironment
• epigenetic alterations
• combination therapy

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Five-year view

Understanding the key aspects in the evolution of cancer cells, which involves the plasticity toward the formation of CSCs, would still remain a code to decipher. Hereby, not only microenvironmental factors mediating epithelial–mesenchymal crosstalk should be taken into consideration as therapeutic targets, also epigenetic factors, which become reexpressed during CSC formation, should be addressed as additional treatment option. In particular, the influence of extracellular molecules in forming CSC niches and of epigenetic changes promoting epithelial cell reprogramming toward a tumor cell population with stem cell-like properties are two points to focus on. The possibility to reverse the CSC phenotype toward a less aggressive, less invasive and druggable tumor cell might be a promising approach for tumor treatment to prevent metastatic spread and tumor recurrences. Hopefully, the new therapeutic strategies will find their way in the clinical routine for patients benefit.

Key issues

• Tumor cell heterogeneity could be defined by inter- and intratumoral genomic alterations as ‘genetic heterogeneity’ as well as by distinct tumor cell populations as ‘phenotypic heterogeneity’.

• The occurrence of different tumor cell populations in the primary tumor is certainly mediated by the tumor cell microenvironment and the reactivation of epigenetic remodeler.

• Identification of pancreatic cancer stem cells and their characteristics, such as self-renewal, increased invasion and metastatic spread, as well as their high tumorigenic potential and drug resistance, point toward their responsibility for tumor recurrence after standard chemotherapy.

• Tumor cell heterogeneity accompanied by drug resistance is a real challenge for therapy, and new mechanisms have to be evolved to overcome the resistance.

• Until now, combinatory therapies with drugs addressing aggressive cancer stem cells (CSCs) directly in combination with standard chemotherapy, such as gemcitabine, showed the most promising results for pancreatic cancer therapy.

• Drugs targeting the epithelial–mesenchymal crosstalk might abolish the CSC niche and prevent the maintenance of the CSC characteristics.

• Epigenetic drugs might be able to reprogram CSCs toward less aggressive, druggable tumor cells.