Human pancreatic cancer progression: an anarchy among CCN-siblings

Abstract

Decades of basic and translational studies have identified the mechanisms by which pancreatic cancer cells use molecular pathways to hijack the normal homeostasis of the pancreas, promoting pancreatic cancer initiation, progression, and metastasis, as well as drug resistance. These molecular pathways were explored to develop targeted therapies to prevent or cure this fatal disease. Regrettably, the studies found that majority of the molecular events that dictate carcinogenic growth in the pancreas are non-actionable (potential non-responder groups of targeted therapy). In this review we discuss exciting discoveries on CCN-siblings that reveal how CCN-family members contribute to the different aspects of the development of pancreatic cancer with special emphasis on therapy.

Keywords: CCN1; CCN2; CCN3; CCN4; CCN5; Genetically engineered mice model; Pancreatic cancer; Patient derived xenograft.

Fig. 1

The molecular domains of CCN-siblings and their functions. The CCN family members (i.e., CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6) share common structure and regulatory domains, consisting of a secretory signal peptide (SP), an IGF-binding domain (Module I), a von Willebrand type C domain (VWC, Module II), a thrombospondin-1 domain (TSP-1, Module III) and a cysteine knot carboxy terminal (CT, Module IV) domain. Domains are linked by hinge regions, susceptible to protease cleavage. Numbers in each module refer to the amino acid (a.a.) sequence for each CCN protein. Integrins binding sites are in the different domains are indicated in the figure. The locations of some important binding partners of each module are indicated by arrow on the top of the diagram: IGF (Insulin like Growth factor, BMP (Bone Morphogenic Protein, TGF-β (Transforming Growth Factor), Integrin, LPR (Lipoprotein Receptor related protein), FN (Fibronectin), Col V (Collagen V), VEGF (Vascular Endothelial Growth Factor), HSPG (Heparin Sulfate Proteoglycan), Notch1 and GF, Growth factor Individual modular domain mediated some cellular functions are listed at the bottom of schematic diagram with respective color coded arrows

Fig. 2

Diagrammatic illustrations of CCN1 signaling involved pancreatic cancer progression via CCN1-Notch1-SHh axes. Our studies postulated that CCN1-mediated pancreatic carcinogenesis is regulated via integrin-αvβ3-Notch-1-SHh signaling pathway in autocrine-paracrine manner. Firstly, Jagged1 is activated by CCN1 which in turn releases an intracellular domain of Notch (ICD) from the membrane into the cytoplasm. CCN1 inhibits the proteasomal degradation process to keep Notch-1(ICD) stable and active in pancreatic cancer cells. CCN1 recruits active ICD into the nucleus to regulate transcriptional complex (TC) for the induction of SHh. SHh binds with its receptor 12-span-transmembrane protein Patched (Ptch1) and relieves another 7-span-transmembrane protein receptor, Smoothened (Smo) inhibition, which in turn induces the signal transduction pathway by activating the nuclear translocation of transcription factor Gli1 protein. Finally, the SHh-Ptch1-Smo-Gli1 signaling pathway promotes pancreatic cancer growth and progression, cell motility, EMT/Stemness and cell proliferation.

Fig. 3

(A) Detection of desmoplasia in orthotopic human PC xenograft mouse model using an ultrasound (Vevo2100)-guided injection (USGI) non-invasive technique, without surgery: Panc-1 aggressive pancreatic cancer cells (1x10⁶) were orthotopically implanted into the mouse pancreas using USGI technique (Huynh et al. 2011). After 2.5 months, tumor growths in the pancreas were detected by ultrasound and then documented after sacrificing the animals. For the detection of DR in PC samples, tissues were fixed in formalin, and H&E staining was carried out in tissue sections. (B) Diagrammatic illustration of Autocrine-paracrine regulation of CCN2 during desmoplasia and chemoresistance

Fig. 4

Diagrammatic representation of CCN5 regulation of invasive phenotypes of pancreatic cancer cells. CCN5 is overexpressed and functionally active in normal microenvironment of pancreatic epithelial cells and its expression could be suppressed in PC cells by mutant p53 gain-of-function. Therapeutic application of CCN5 or ectopic overexpression of CCN5 suppresses EMTosomes (regulators of EMT) activity resulted reverses invasive phenotypes of PC cells