Limits...
Tissue and Serum microRNAs in the KrasG12D Transgenic Animal Model and in Patients with Pancreatic Cancer

LaConti JJ, Shivapurkar N, Preet A, Deslattes Mays A, Peran I, Kim SE, Marshall JL, Riegel AT, Wellstein A - PLoS ONE (2011)

Bottom Line: Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated.Finally, gemcitabine treatment of control animals and p48-Cre/LSL-Kras(G12D) animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues.These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.

Affiliation: Lombardi Cancer Center, Georgetown University, Washington, DC, United States of America.

ABSTRACT

microRNAs (miRs) modulate the expression levels of mRNAs and proteins and can thus contribute to cancer initiation and progression. In addition to their intracelluar function, miRs are released from cells and shed into the circulation. We postulated that circulating miRs could provide insight into pathways altered during cancer progression and may indicate responses to treatment. Here we focus on pancreatic cancer malignant progression. We report that changes in miR expression patterns during progression of normal tissues to invasive pancreatic adenocarcinoma in the p48-Cre/LSL-Kras(G12D) mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a/b and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated. Quantitation of nine microRNAs in plasma samples from patients distinguished pancreatic cancers from other cancers as well as non-cancerous pancreatic disease. Finally, gemcitabine treatment of control animals and p48-Cre/LSL-Kras(G12D) animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues. These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.

Malignant progression of pancreatic duct epithelia in p48-Cre/LSL-KrasG12D mice.(A) Quantitation of histopathologic alterations in the pancreata of controls or p48-Cre/KrasG12D mice. The samples were separated into controls, early stage dysplastic lesions (PanIN-1 and -2), late stage dysplastic lesions (PanIN-3 present) and invasive pancreatic duct adenocarcinoma (PDAC). (B to E) Representative histopathology images from each of the groups: (B) normal pancreas, (C) PanIN-1 and -2 (early), (D) PanIN-3 (late) and (E) PDAC. Mean ± standard error of the % of the pancreatic tissue with the respective lesions is shown (n = 3 animals for each group). 0, not detected.
© Copyright Policy

pone-0020687-g001: Malignant progression of pancreatic duct epithelia in p48-Cre/LSL-KrasG12D mice.(A) Quantitation of histopathologic alterations in the pancreata of controls or p48-Cre/KrasG12D mice. The samples were separated into controls, early stage dysplastic lesions (PanIN-1 and -2), late stage dysplastic lesions (PanIN-3 present) and invasive pancreatic duct adenocarcinoma (PDAC). (B to E) Representative histopathology images from each of the groups: (B) normal pancreas, (C) PanIN-1 and -2 (early), (D) PanIN-3 (late) and (E) PDAC. Mean ± standard error of the % of the pancreatic tissue with the respective lesions is shown (n = 3 animals for each group). 0, not detected.

Mentions: Mouse pancreatic tissue samples were harvested at different ages from the p48-Cre/LSL-KrasG12D mouse model. Pancreatic duct epithelia in these animals progress through early and late dysplastic lesions, PanIN ( = Pancreatic in situ carcinoma) over the period of several months to invasive cancer and thus mimic malignant progression of the human disease [34], [35]. Each tissue sample harvested was staged by a histologic analysis of pancreatic ductal changes (Figure 1A). Control tissues contained 100% normal ducts (Figure 1B). Pancreata from younger mice (Figure 1C) contained more than 50% of ducts with early stage dysplastic lesions (PanIN-1 or -2). Pancreata from older mice (Figure 1D) contained ∼10% of ducts with late stage dysplastic lesions (PanIN-3) in addition to ∼50% of ducts with PanIN-1 or -2. PDAC tissues contained mostly invasive adenocarcinoma (Figure 1E).

View Similar Images In: Results  - Collection
View Article: Pubmed Central -  PubMed
Show All Figures - Show MeSH
getmorefigures.php?pmc=3124473&rFormat=json&query=null&req=5
Tissue and Serum microRNAs in the KrasG12D Transgenic Animal Model and in Patients with Pancreatic Cancer

LaConti JJ, Shivapurkar N, Preet A, Deslattes Mays A, Peran I, Kim SE, Marshall JL, Riegel AT, Wellstein A - PLoS ONE (2011)

Malignant progression of pancreatic duct epithelia in p48-Cre/LSL-KrasG12D mice.(A) Quantitation of histopathologic alterations in the pancreata of controls or p48-Cre/KrasG12D mice. The samples were separated into controls, early stage dysplastic lesions (PanIN-1 and -2), late stage dysplastic lesions (PanIN-3 present) and invasive pancreatic duct adenocarcinoma (PDAC). (B to E) Representative histopathology images from each of the groups: (B) normal pancreas, (C) PanIN-1 and -2 (early), (D) PanIN-3 (late) and (E) PDAC. Mean ± standard error of the % of the pancreatic tissue with the respective lesions is shown (n = 3 animals for each group). 0, not detected.
© Copyright Policy
pone-0020687-g001: Malignant progression of pancreatic duct epithelia in p48-Cre/LSL-KrasG12D mice.(A) Quantitation of histopathologic alterations in the pancreata of controls or p48-Cre/KrasG12D mice. The samples were separated into controls, early stage dysplastic lesions (PanIN-1 and -2), late stage dysplastic lesions (PanIN-3 present) and invasive pancreatic duct adenocarcinoma (PDAC). (B to E) Representative histopathology images from each of the groups: (B) normal pancreas, (C) PanIN-1 and -2 (early), (D) PanIN-3 (late) and (E) PDAC. Mean ± standard error of the % of the pancreatic tissue with the respective lesions is shown (n = 3 animals for each group). 0, not detected.
Mentions: Mouse pancreatic tissue samples were harvested at different ages from the p48-Cre/LSL-KrasG12D mouse model. Pancreatic duct epithelia in these animals progress through early and late dysplastic lesions, PanIN ( = Pancreatic in situ carcinoma) over the period of several months to invasive cancer and thus mimic malignant progression of the human disease [34], [35]. Each tissue sample harvested was staged by a histologic analysis of pancreatic ductal changes (Figure 1A). Control tissues contained 100% normal ducts (Figure 1B). Pancreata from younger mice (Figure 1C) contained more than 50% of ducts with early stage dysplastic lesions (PanIN-1 or -2). Pancreata from older mice (Figure 1D) contained ∼10% of ducts with late stage dysplastic lesions (PanIN-3) in addition to ∼50% of ducts with PanIN-1 or -2. PDAC tissues contained mostly invasive adenocarcinoma (Figure 1E).

Bottom Line: Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated.Finally, gemcitabine treatment of control animals and p48-Cre/LSL-Kras(G12D) animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues.These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.

Affiliation: Lombardi Cancer Center, Georgetown University, Washington, DC, United States of America.

ABSTRACT

Background: microRNAs (miRs) modulate the expression levels of mRNAs and proteins and can thus contribute to cancer initiation and progression. In addition to their intracelluar function, miRs are released from cells and shed into the circulation. We postulated that circulating miRs could provide insight into pathways altered during cancer progression and may indicate responses to treatment. Here we focus on pancreatic cancer malignant progression. We report that changes in miR expression patterns during progression of normal tissues to invasive pancreatic adenocarcinoma in the p48-Cre/LSL-Kras(G12D) mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a/b and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated. Quantitation of nine microRNAs in plasma samples from patients distinguished pancreatic cancers from other cancers as well as non-cancerous pancreatic disease. Finally, gemcitabine treatment of control animals and p48-Cre/LSL-Kras(G12D) animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues. These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.

View Similar Images In: Results  - Collection
View Article: Pubmed Central -  PubMed
Show All Figures - Show MeSH
getmorefigures.php?pmc=3124473&rFormat=json&query=null&req=5