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Deciphering the cellular source of tumor relapse identifies CD44 as a major therapeutic target in pancreatic adenocarcinoma.

Molejon MI, Tellechea JI, Loncle C, Gayet O, Gilabert M, Duconseil P, Lopez-Millan MB, Moutardier V, Gasmi M, Garcia S, Turrini O, Ouaissi M, Poizat F, Dusetti N, Iovanna J - Oncotarget (2015)

Bottom Line: The origin and biological characteristics of residual tumor cells in PDAC still remain unclear.During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation.We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.

ABSTRACT
It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC.

No MeSH data available.


Related in: MedlinePlus

CD44 expression in human samples(A) CD44 expression was evaluated in human PDACs before and after chemotherapy. A magnification is shown on the right side of the figure. (B) Quantification of CD44-positive cells from. (C) Quantification of CD44-positive cells from 15 non-treated patients (Primary Tumor) and 15 chemotherapy treated patients (Residual Tumor) is shown. Scale bar represents 50 μm. Error bars ± SEM; n=15 per group. **P<0.001 compared to samples before treatment.
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Figure 7: CD44 expression in human samples(A) CD44 expression was evaluated in human PDACs before and after chemotherapy. A magnification is shown on the right side of the figure. (B) Quantification of CD44-positive cells from. (C) Quantification of CD44-positive cells from 15 non-treated patients (Primary Tumor) and 15 chemotherapy treated patients (Residual Tumor) is shown. Scale bar represents 50 μm. Error bars ± SEM; n=15 per group. **P<0.001 compared to samples before treatment.

Mentions: Finally, we studied CD44 expression in human PDACs. We collected 4 PDAC samples from the surgery of 2 patients who were deemed non-resectable after their cancers were found to be locally advanced. These patients underwent standard gemcitabine-based treatment, which allowed subsequent successful resection of their tumors, from which we obtained further PDAC samples. Therefore these samples allowed us the rare opportunity to compare PDAC samples from the same patients, before and after chemotherapy. Immunohistochemical analysis of CD44 expression showed that CD44+ cells were almost undetectable in tumorigenic cells from pretreated samples, whereas these cells were dominant after gemcitabine administration, as showed in Figure 7A. We then evaluated an additional set of 15 surgical samples from non-treated patients and 15 samples which were obtained after gemcitabine-based chemotherapy, and found similar results, as showed in Figure 7C. The findings obtained from human specimens collectively support our xenograft results, suggesting that CD44 could be an efficient therapeutic target for the treatment of residual but not primary human PDAC.


Deciphering the cellular source of tumor relapse identifies CD44 as a major therapeutic target in pancreatic adenocarcinoma.

Molejon MI, Tellechea JI, Loncle C, Gayet O, Gilabert M, Duconseil P, Lopez-Millan MB, Moutardier V, Gasmi M, Garcia S, Turrini O, Ouaissi M, Poizat F, Dusetti N, Iovanna J - Oncotarget (2015)

CD44 expression in human samples(A) CD44 expression was evaluated in human PDACs before and after chemotherapy. A magnification is shown on the right side of the figure. (B) Quantification of CD44-positive cells from. (C) Quantification of CD44-positive cells from 15 non-treated patients (Primary Tumor) and 15 chemotherapy treated patients (Residual Tumor) is shown. Scale bar represents 50 μm. Error bars ± SEM; n=15 per group. **P<0.001 compared to samples before treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480689&req=5

Figure 7: CD44 expression in human samples(A) CD44 expression was evaluated in human PDACs before and after chemotherapy. A magnification is shown on the right side of the figure. (B) Quantification of CD44-positive cells from. (C) Quantification of CD44-positive cells from 15 non-treated patients (Primary Tumor) and 15 chemotherapy treated patients (Residual Tumor) is shown. Scale bar represents 50 μm. Error bars ± SEM; n=15 per group. **P<0.001 compared to samples before treatment.
Mentions: Finally, we studied CD44 expression in human PDACs. We collected 4 PDAC samples from the surgery of 2 patients who were deemed non-resectable after their cancers were found to be locally advanced. These patients underwent standard gemcitabine-based treatment, which allowed subsequent successful resection of their tumors, from which we obtained further PDAC samples. Therefore these samples allowed us the rare opportunity to compare PDAC samples from the same patients, before and after chemotherapy. Immunohistochemical analysis of CD44 expression showed that CD44+ cells were almost undetectable in tumorigenic cells from pretreated samples, whereas these cells were dominant after gemcitabine administration, as showed in Figure 7A. We then evaluated an additional set of 15 surgical samples from non-treated patients and 15 samples which were obtained after gemcitabine-based chemotherapy, and found similar results, as showed in Figure 7C. The findings obtained from human specimens collectively support our xenograft results, suggesting that CD44 could be an efficient therapeutic target for the treatment of residual but not primary human PDAC.

Bottom Line: The origin and biological characteristics of residual tumor cells in PDAC still remain unclear.During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation.We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.

ABSTRACT
It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC.

No MeSH data available.


Related in: MedlinePlus