Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer

Abstract

Pancreatic cancer is one of the most fatal human malignancies. Though a relatively rare malignancy, it remains one of the deadliest tumors, with an extremely high mortality rate. The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Tumor-specific targeted therapy is a relatively recent addition to the arsenal of anti-cancer therapies. It is important to find novel targets to distinguish tumor cells from their normal counterparts in therapeutic approaches. In the past few decades, studies have revealed the molecular mechanisms of pancreatic tumorigenesis, growth, invasion and metastasis. The proteins that participate in the pathophysiological processes of pancreatic cancer might be potential targets for therapy. This review describes the main players in perineural invasion, hypoxia and desmoplasia and the molecular mechanisms of these pathophysiological processes.

Fig. (1). The interaction between neural cells and cancer cells in the generation of perineural invasion (PNI) in pancreatic cancer

Several neurotrophic factors (e.g., NGF, GDNF, BDNF), chemokines (e.g., CSF, CX3CL1), neurotransmitters (e.g., substance P) and cell-surface molecules (e.g., NCAM, MAG) are involved in neuro-cancer interactions. Growth factors secreted by cancer cells attract neural fibers to grow towards and into the cancer. Simultaneously, molecular factors derived from neural tissues induce the proliferation and direct the migration of cancer cells. (C, cancer cells; N, neural fiber)

Fig. (2). HIF-1α is the key factor in hypoxia response

Hypoxic conditions can lead to several cellular and molecular changes, many of which are transduced through the basic helix-loop-helix transcription factor HIF-1α. Under normal oxygen conditions, the HIF-1α protein is rapidly ubiquitinated and degraded. Under hypoxic conditions, the protein is stabilized, heterodimerizes with ARNT, and translocates to the nucleus where it activates transcription from a number of hypoxia-responsive genes.

Fig. (3). Interaction of PSCs with pancreatic cancer cells

Cancer cells accelerate transformation of quiescent PSCs to an activated phenotype in a paracrine manner. Activated PSCs are attracted by cancers and stimulated to proliferate and produce ECM and growth factors. Further, PSCs stimulate the proliferation, chemoresistance, invasion, and motility of pancreatic cancers. (P, pancreatic acinar; F, stroma fibrosis; C, cancer cells)