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MMP-13 In-Vivo Molecular Imaging Reveals Early Expression in Lung Adenocarcinoma.

Salaün M, Peng J, Hensley HH, Roder N, Flieder DB, Houlle-Crépin S, Abramovici-Roels O, Sabourin JC, Thiberville L, Clapper ML - PLoS ONE (2015)

Bottom Line: The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells.In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors.In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001).

View Article: PubMed Central - PubMed

Affiliation: Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America; Laboratoire Quant.I.F - LITIS, EA 4108, Rouen University, Rouen, France; Clinique Pneumologique & CIC INSERM U1404, Rouen University Hospital, Rouen, France.

ABSTRACT

Introduction: Several matrix metalloproteinases (MMPs) are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging.

Objective: To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma.

Methods: K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT) and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors.

Results: In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001).

Conclusion: MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer.

No MeSH data available.


Related in: MedlinePlus

The fluorescent signal from MMPs increases in lung tumors.A)Ex vivo image of MMP activity in superficial lung lesions of various stages from K-rasLSL-G12D mice. The nonneoplastic lobe (L1) of freshly isolated lungs imaged immediately after euthanasia did not display any fluorescent signal, while in the tumor-bearing lobes (L2-5), signal increased with the degree of lesion severity. The data confirmed the ability of an epi-illumination fluorescence system (IVIS Spectrum) to image MMP activity at different stages of lung tumor progression. B) Fluorescence intensity of lung adenomas (n = 8), adenocarcinomas (n = 3) and normal lung lobes (n = 25). In this experiment, the lung and tumor fluorescence signal was normalized on liver fluorescence, based on the hepatic activation of the probe. The fluorescence intensity ratio was calculated as a ratio of the median radiant efficiency of the lung lobe / liver. The median values ± interquartile range are shown, and the median differences between cancerous lesions and normal lobes are significant. * p value <0.05 by the Mann-Whitney test.
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pone.0132960.g002: The fluorescent signal from MMPs increases in lung tumors.A)Ex vivo image of MMP activity in superficial lung lesions of various stages from K-rasLSL-G12D mice. The nonneoplastic lobe (L1) of freshly isolated lungs imaged immediately after euthanasia did not display any fluorescent signal, while in the tumor-bearing lobes (L2-5), signal increased with the degree of lesion severity. The data confirmed the ability of an epi-illumination fluorescence system (IVIS Spectrum) to image MMP activity at different stages of lung tumor progression. B) Fluorescence intensity of lung adenomas (n = 8), adenocarcinomas (n = 3) and normal lung lobes (n = 25). In this experiment, the lung and tumor fluorescence signal was normalized on liver fluorescence, based on the hepatic activation of the probe. The fluorescence intensity ratio was calculated as a ratio of the median radiant efficiency of the lung lobe / liver. The median values ± interquartile range are shown, and the median differences between cancerous lesions and normal lobes are significant. * p value <0.05 by the Mann-Whitney test.

Mentions: Initial experiments were performed using an epi-illumination fluorescence imaging system (IVIS Spectrum) to determine the feasibility of detecting MMP activity in lung tumors in the K-rasLSL-G12D model. In this experiment, five K-rasLSL-G12D mice (3 with 8 adenomas and 2 with 3 adenocarcinomas) and five wild-type control mice were instilled with the AdenoCre virus. Following injection of MMPSense680, mice were subjected to whole body imaging using the IVIS Spectrum. Only very large tumors (> 10 mm) were detectable in vivo with the epi-illumination imaging system (Fig 1). The technique was not sensitive enough to identify smaller lung tumors or specific lesions due to the lack of spatial resolution of deeply embedded tumors. However, tumors representative of all stages of the adenoma to carcinoma sequence were detected ex vivo (Fig 2). The fluorescence intensity increased significantly in adenomas and adenocarcinomas, as compared to normal lung tissue (Fig 2B). These experiments confirm the feasibility of imaging MMPs in lung tumors in the K-rasLSL-G12D model, and demonstrate the reliability of the method to image the continuum for lung carcinogenesis.


MMP-13 In-Vivo Molecular Imaging Reveals Early Expression in Lung Adenocarcinoma.

Salaün M, Peng J, Hensley HH, Roder N, Flieder DB, Houlle-Crépin S, Abramovici-Roels O, Sabourin JC, Thiberville L, Clapper ML - PLoS ONE (2015)

The fluorescent signal from MMPs increases in lung tumors.A)Ex vivo image of MMP activity in superficial lung lesions of various stages from K-rasLSL-G12D mice. The nonneoplastic lobe (L1) of freshly isolated lungs imaged immediately after euthanasia did not display any fluorescent signal, while in the tumor-bearing lobes (L2-5), signal increased with the degree of lesion severity. The data confirmed the ability of an epi-illumination fluorescence system (IVIS Spectrum) to image MMP activity at different stages of lung tumor progression. B) Fluorescence intensity of lung adenomas (n = 8), adenocarcinomas (n = 3) and normal lung lobes (n = 25). In this experiment, the lung and tumor fluorescence signal was normalized on liver fluorescence, based on the hepatic activation of the probe. The fluorescence intensity ratio was calculated as a ratio of the median radiant efficiency of the lung lobe / liver. The median values ± interquartile range are shown, and the median differences between cancerous lesions and normal lobes are significant. * p value <0.05 by the Mann-Whitney test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4508003&req=5

pone.0132960.g002: The fluorescent signal from MMPs increases in lung tumors.A)Ex vivo image of MMP activity in superficial lung lesions of various stages from K-rasLSL-G12D mice. The nonneoplastic lobe (L1) of freshly isolated lungs imaged immediately after euthanasia did not display any fluorescent signal, while in the tumor-bearing lobes (L2-5), signal increased with the degree of lesion severity. The data confirmed the ability of an epi-illumination fluorescence system (IVIS Spectrum) to image MMP activity at different stages of lung tumor progression. B) Fluorescence intensity of lung adenomas (n = 8), adenocarcinomas (n = 3) and normal lung lobes (n = 25). In this experiment, the lung and tumor fluorescence signal was normalized on liver fluorescence, based on the hepatic activation of the probe. The fluorescence intensity ratio was calculated as a ratio of the median radiant efficiency of the lung lobe / liver. The median values ± interquartile range are shown, and the median differences between cancerous lesions and normal lobes are significant. * p value <0.05 by the Mann-Whitney test.
Mentions: Initial experiments were performed using an epi-illumination fluorescence imaging system (IVIS Spectrum) to determine the feasibility of detecting MMP activity in lung tumors in the K-rasLSL-G12D model. In this experiment, five K-rasLSL-G12D mice (3 with 8 adenomas and 2 with 3 adenocarcinomas) and five wild-type control mice were instilled with the AdenoCre virus. Following injection of MMPSense680, mice were subjected to whole body imaging using the IVIS Spectrum. Only very large tumors (> 10 mm) were detectable in vivo with the epi-illumination imaging system (Fig 1). The technique was not sensitive enough to identify smaller lung tumors or specific lesions due to the lack of spatial resolution of deeply embedded tumors. However, tumors representative of all stages of the adenoma to carcinoma sequence were detected ex vivo (Fig 2). The fluorescence intensity increased significantly in adenomas and adenocarcinomas, as compared to normal lung tissue (Fig 2B). These experiments confirm the feasibility of imaging MMPs in lung tumors in the K-rasLSL-G12D model, and demonstrate the reliability of the method to image the continuum for lung carcinogenesis.

Bottom Line: The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells.In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors.In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001).

View Article: PubMed Central - PubMed

Affiliation: Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America; Laboratoire Quant.I.F - LITIS, EA 4108, Rouen University, Rouen, France; Clinique Pneumologique & CIC INSERM U1404, Rouen University Hospital, Rouen, France.

ABSTRACT

Introduction: Several matrix metalloproteinases (MMPs) are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging.

Objective: To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma.

Methods: K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT) and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors.

Results: In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001).

Conclusion: MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer.

No MeSH data available.


Related in: MedlinePlus