Pancreatic cancer: disease dynamics, tumor biology and the role of the microenvironment

Abstract

Pancreatic cancer is known for its propensity to metastasize. Recent studies have challenged the commonly held belief that pancreatic cancer is a stepwise process, where tumor cells disseminate late in primary tumor development. Instead it has been suggested that pancreatic tumor cells may disseminate early and develop independently and in parallel to the primary tumor. Circulating tumor cells can be found in most patients with pancreatic cancer, even in those with localized stage. Also, recent phylogenetic analyses have revealed evidence for a branched evolution where metastatic lineages can develop early in tumor development. In this Review, we discuss current models of pancreatic cancer progression and the importance of the tumor microenvironment, in order to better understand the recalcitrant nature of this disease.

Keywords: disease dynamics; microenvironment; pancreatic cancer; tumor biology.

Figure 1. Traditional model of pancreatic cancer progression

In the linear progression model accumulation of genetic and epigenetic changes occurs over a long period of time and metastases develop in a late phase when the tumor has reached a detectable size.

Figure 2. Alternative model of pancreatic cancer progression

Tumor cells disseminate at any point of tumor progression and develop independently into metastases in parallel to the primary tumor.

Figure 3. Early resection of the primary tumor without detectable metastases prevents further tumor growth and thereby further tumor dissemination and prolongs survival

Unfortunately, not even a radical surgery prevents development of potential metastases from early disseminated cancer cells.

Figure 4. The microenvironment regulates pancreatic cancer progression and metastasis

Tumor-derived exosomes, bone marrow-derived cells and local stromal components promote metastasis by inducing pre-metastatic niches in distant organs, which are conducive to the survival and outgrowth of tumor cells before their arrival at these sites. BMDC: bone marrow-derived cell; CAF: cancer-associated fibroblast; ECM: extracellular matrix; MDSC: myeloid-derived suppressor cell; TAM: tumor-associated macrophage.