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Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer.

Zhang Y, Liu L, Fan P, Bauer N, Gladkich J, Ryschich E, Bazhin AV, Giese NA, Strobel O, Hackert T, Hinz U, Gross W, Fortunato F, Herr I - Oncotarget (2015)

Bottom Line: Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling.Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine.Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice.

View Article: PubMed Central - PubMed

Affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.

No MeSH data available.


Related in: MedlinePlus

Aspirin intake before surgery inhibits the expression of progression markers in PDA patient tissueTumor tissue sections derived from patients with documented pre-operative administration of aspirin (n = 7), gemcitabine (n = 5), aspirin plus gemcitabine (n = 3), or neither aspirin nor gemcitabine (n = 6) were evaluated by immunohistochemistry for the expression of the proliferation marker Ki67, the inflammatory factor TNF-α, and the CSC markers c-Met, CD44 and CXCR4. The scale bar indicates 50 μm. The number of positive cells was quantified in 10 visual fields at 400× magnification, and the means ± SD are shown in the diagrams. The data are presented as means ± SD (**P < 0.01, *P < 0.05).
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Figure 7: Aspirin intake before surgery inhibits the expression of progression markers in PDA patient tissueTumor tissue sections derived from patients with documented pre-operative administration of aspirin (n = 7), gemcitabine (n = 5), aspirin plus gemcitabine (n = 3), or neither aspirin nor gemcitabine (n = 6) were evaluated by immunohistochemistry for the expression of the proliferation marker Ki67, the inflammatory factor TNF-α, and the CSC markers c-Met, CD44 and CXCR4. The scale bar indicates 50 μm. The number of positive cells was quantified in 10 visual fields at 400× magnification, and the means ± SD are shown in the diagrams. The data are presented as means ± SD (**P < 0.01, *P < 0.05).

Mentions: To examine the impact of aspirin in PDA patients, we examined tissues from patients that had taken aspirin (n = 5), gemcitabine (n = 4), both together (n = 3) or neither (n = 4) prior to resection (compare Table 1). In accordance with the former in ovo and mouse xenograft results, aspirin intake reduced the expression of Ki67, c-Met, CxCR4, CD44, and TNF-α (Figure 7). Because a recent multicenter retrospective study suggested a reduction in liver fibrosis mediated by aspirin [31], we examined the effect of aspirin on the deposition of collagen fibers in pancreatic tissues by trichrome staining and immunohistochemistry. Aspirin intake inhibited collagen deposition, whereas gemcitabine had no effect. However, the combination treatment resembled aspirin treatment alone, as observed in 3 representative sets of patient tissues (Figure 8A). Likewise, the expression of αSMA, which marks active, collagen-producing stellate cells, was strongly inhibited by both aspirin and gemcitabine, although no additional effect was observed with combination treatment (Figure 8B). These results strongly point to the direction, that aspirin may prevent progression of PDA by inhibition of the inflammatory response and thus the desmoplastic reaction.


Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer.

Zhang Y, Liu L, Fan P, Bauer N, Gladkich J, Ryschich E, Bazhin AV, Giese NA, Strobel O, Hackert T, Hinz U, Gross W, Fortunato F, Herr I - Oncotarget (2015)

Aspirin intake before surgery inhibits the expression of progression markers in PDA patient tissueTumor tissue sections derived from patients with documented pre-operative administration of aspirin (n = 7), gemcitabine (n = 5), aspirin plus gemcitabine (n = 3), or neither aspirin nor gemcitabine (n = 6) were evaluated by immunohistochemistry for the expression of the proliferation marker Ki67, the inflammatory factor TNF-α, and the CSC markers c-Met, CD44 and CXCR4. The scale bar indicates 50 μm. The number of positive cells was quantified in 10 visual fields at 400× magnification, and the means ± SD are shown in the diagrams. The data are presented as means ± SD (**P < 0.01, *P < 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496413&req=5

Figure 7: Aspirin intake before surgery inhibits the expression of progression markers in PDA patient tissueTumor tissue sections derived from patients with documented pre-operative administration of aspirin (n = 7), gemcitabine (n = 5), aspirin plus gemcitabine (n = 3), or neither aspirin nor gemcitabine (n = 6) were evaluated by immunohistochemistry for the expression of the proliferation marker Ki67, the inflammatory factor TNF-α, and the CSC markers c-Met, CD44 and CXCR4. The scale bar indicates 50 μm. The number of positive cells was quantified in 10 visual fields at 400× magnification, and the means ± SD are shown in the diagrams. The data are presented as means ± SD (**P < 0.01, *P < 0.05).
Mentions: To examine the impact of aspirin in PDA patients, we examined tissues from patients that had taken aspirin (n = 5), gemcitabine (n = 4), both together (n = 3) or neither (n = 4) prior to resection (compare Table 1). In accordance with the former in ovo and mouse xenograft results, aspirin intake reduced the expression of Ki67, c-Met, CxCR4, CD44, and TNF-α (Figure 7). Because a recent multicenter retrospective study suggested a reduction in liver fibrosis mediated by aspirin [31], we examined the effect of aspirin on the deposition of collagen fibers in pancreatic tissues by trichrome staining and immunohistochemistry. Aspirin intake inhibited collagen deposition, whereas gemcitabine had no effect. However, the combination treatment resembled aspirin treatment alone, as observed in 3 representative sets of patient tissues (Figure 8A). Likewise, the expression of αSMA, which marks active, collagen-producing stellate cells, was strongly inhibited by both aspirin and gemcitabine, although no additional effect was observed with combination treatment (Figure 8B). These results strongly point to the direction, that aspirin may prevent progression of PDA by inhibition of the inflammatory response and thus the desmoplastic reaction.

Bottom Line: Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling.Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine.Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice.

View Article: PubMed Central - PubMed

Affiliation: Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

ABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis. An inflammatory microenvironment triggers the pronounced desmoplasia, the selection of cancer stem-like cells (CSCs) and therapy resistance. The anti-inflammatory drug aspirin is suggested to lower the risk for PDA and to improve the treatment, although available results are conflicting and the effect of aspirin to CSC characteristics and desmoplasia in PDA has not yet been investigated. We characterized the influence of aspirin on CSC features, stromal reactions and gemcitabine resistance. Four established and 3 primary PDA cell lines, non-malignant cells, 3 patient tumor-derived CSC-enriched spheroidal cultures and tissues from patients who did or did not receive aspirin before surgery were analyzed using MTT assays, flow cytometry, colony and spheroid formation assays, Western blot analysis, antibody protein arrays, electrophoretic mobility shift assays (EMSAs), immunohistochemistry and in vivo xenotransplantation. Aspirin significantly induced apoptosis and reduced the viability, self-renewal potential, and expression of proteins involved in inflammation and stem cell signaling. Aspirin also reduced the growth and invasion of tumors in vivo, and it significantly prolonged the survival of mice with orthotopic pancreatic xenografts in combination with gemcitabine. This was associated with a decreased expression of markers for progression, inflammation and desmoplasia. These findings were confirmed in tissue samples obtained from patients who had or had not taken aspirin before surgery. Importantly, aspirin sensitized cells that were resistant to gemcitabine and thereby enhanced the therapeutic efficacy. Aspirin showed no obvious toxic effects on normal cells, chick embryos or mice. These results highlight aspirin as an effective, inexpensive and well-tolerated co-treatment to target inflammation, desmoplasia and CSC features PDA.

No MeSH data available.


Related in: MedlinePlus