Pancreatic cancer and its stroma: a conspiracy theory

Abstract

Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells (pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biology and the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.

Keywords: Metastasis; Pancreatic cancer; Pancreatic stellate cells; Stromal reaction; Tumour-stroma interactions.

Figure 1

Pancreatic cancer and stromal reaction. A representative HE stained human pancreatic cancer tissue section showing duct-like and tubular structures (malignant elements, examples highlighted by arrows) infiltrating into and embedded in a highly fibrotic stromal reaction (examples highlighted by asterisks).

Figure 2

Pancreatic stellate cells are the source of collagen in stroma. A: A representative pair of serial sections of human pancreatic cancer tissue shows that Sirius Red staining for collagen (red) co-localises with immunohistochemical staining for α-smooth muscle actin (α-SMA) (brown), suggesting the presence of activated pancreatic stellate cells (PSCs) in the stroma of pancreatic cancer[33]. Reprinted with permission from Wolters Kluwer Health (Apte et al[33]); B: Immunohistochemistry for α-SMA (brown) and in situ hybridisation for procollagen α1 mRNA (blue), reveals colocalisation of α-SMA and procollagen mRNA on human pancreatic cancer tissue indicating that active PSCs are the major source of collagen in tumour stroma. Reprinted with permission from Elsevier (Apte et al[43]).

Figure 3

Interaction between pancreatic cancer cells and pancreatic stellate cells. Pancreatic cancer cells stimulate the proliferation, extracellular matrix (ECM) production, angiogenic factors and matrix metalloproteinase (MMP) expression, as well as migration of pancreatic stellate cells (PSCs); conversely PSCs increase proliferation and reduce apoptosis leading to increased survival, increase cancer cell migration and facilitate a cancer stem cell niche. The overall effect of interaction between pancreatic cancer cells and PSCs facilitates cancer progression[43].

Figure 4

Identification of human pancreatic stellate cells from primary tumour in metastatic nodules. A representative photomicrograph showing Y chromosome positive cells in metastatic nodules in the mesentery (inserts are high power views of the circled regions), liver and diaphragm from mice (female) injected with female pancreatic cancer cells + male human pancreatic stellate cells, using fluorescent in situ hybridisation for the Y chromosome. Reprinted with permission from Elsevier (Xu et al[63]).

Figure 5

Tumour components. The stromal reaction of pancreatic ductal adenocarcinoma is comprised of pancreatic stellate cells (stromal cells), abundant extracellular matrix (ECM), blood vessels/endothelial cells, immune cells and nerves/neurons[43]. The interaction between cancer cells and the components of stroma facilitates cancer progression. Reprinted with permission from Elsevier (Apte et al[43]).