Abstract
Cancer stem cells (CSCs) subpopulation within the tumour is responsible for metastasis and cancer relapse. Here we investigate in vitro and in vivo the effects of a pancreatic (pro)enzyme mixture composed of Chymotrypsinogen and Trypsinogen (PRP) on CSCs derived from a human pancreatic cell line, BxPC3. Exposure of pancreatic CSCs spheres to PRP resulted in a significant decrease of ALDEFLUOR and specific pancreatic CSC markers (CD 326, CD 44 and CxCR4) signal tested by flow cytometry, further CSCs markers expression was also analyzed by western and immunofluorescence assays. PRP also inhibits primary and secondary sphere formation. Three RT2 Profiler PCR Arrays were used to study gene expression regulation after PRP treatment and resulted in, (i) epithelial-mesenchymal transition (EMT) inhibition; (ii) CSCs related genes suppression; (iii) enhanced expression of tumour suppressor genes; (iv) downregulation of migration and metastasis genes and (v) regulation of MAP Kinase Signalling Pathway. Finally, in vivo anti-tumor xenograft studies demonstrated high anti-tumour efficacy of PRP against tumours induced by BxPC3 human pancreatic CSCs. PRP impaired engrafting of pancreatic CSC’s tumours in nude mice and displayed an antigrowth effect toward initiated xenografts. We concluded that (pro)enzymes treatment is a valuable strategy to suppress the CSC population in solid pancreatic tumours.
Highlights
Improving therapies against hematopoietic malignancies and solid tumours are making cancer a chronic disease and represent a short-term success
We have analysed with RT2 Profiler PCR Arrays changes of expression of genes involved in epithelialmesenchymal transition (EMT) or related to Cancer stem cells (CSCs) and MAP Kinase Signalling Pathway induced by PRP treatment
We further determine the expression of the pancreatic cancer markers CD44, CD326 and CxCR4 by immunofluorescence (Fig. 1C) and by western blotting (Fig. 1D and Supplementary Fig. S1)
Summary
Improving therapies against hematopoietic malignancies and solid tumours are making cancer a chronic disease and represent a short-term success. The discovery of a subpopulation of cells with stem cell-like features, called cancer stem cells (CSCs), in a wide spectrum of solid tumours[1] has led to a new model of tumorigenesis, the CSCs hypothesis This model suggests that the intrinsic characteristics of these cells, such as self-renewal and the ability to differentiate, drive tumour initiation and progression, and the subsequent chance of developing metastasis and tumour recurrence[2]. Previous research has suggested a putative utility of pancreatic (pro)enzymes in cancer treatment[7,8] In agreement with these studies, we have shown in vivo and in vitro the anti-tumour efficacy of a novel pro-enzyme formulation consisting of a combination of Trypsinogen and Chymotrypsinogen A (PRP), that proves to be an effective and non-toxic treatment, able to induce lineage specific cellular differentiation, inhibit angiogenesis, tumour growth, cancer cell migration and invasiveness. We have conducted a xenograft study to assess the effect of PRP in suppressing tumour growth in vivo
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