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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

CSC-associated marker expression in vitro and its relationship to chemosensitivity(A) Flow cytometry was performed to identify quadruple staining for CD44-APC, EpCAM-VioBlue, CD24-PE and ALDH-FITC in fourteen primary cell-derived xenografts (n = 3). (B) Each cell line was treated with increasing concentrations (from 0 to 1000 μM) of Gemcitabine, Docetaxel (TXT), 5-Fluouracil (5FU), Oxaliplatin and the active metabolite of Irinotecan known as SN-38. The rate of cell survival was measured after 72 h of treatment. A sensitivity profile was obtained for each drug and the IC50 data is presented in the table. (C) Linear regression analysis to assess the level of expression of each CSC-associated marker and IC50 corresponding to each drug, was performed. N=3 per group.
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Figure 4: CSC-associated marker expression in vitro and its relationship to chemosensitivity(A) Flow cytometry was performed to identify quadruple staining for CD44-APC, EpCAM-VioBlue, CD24-PE and ALDH-FITC in fourteen primary cell-derived xenografts (n = 3). (B) Each cell line was treated with increasing concentrations (from 0 to 1000 μM) of Gemcitabine, Docetaxel (TXT), 5-Fluouracil (5FU), Oxaliplatin and the active metabolite of Irinotecan known as SN-38. The rate of cell survival was measured after 72 h of treatment. A sensitivity profile was obtained for each drug and the IC50 data is presented in the table. (C) Linear regression analysis to assess the level of expression of each CSC-associated marker and IC50 corresponding to each drug, was performed. N=3 per group.

Mentions: The association between chemoresistance and CSC marker expression in vitro has been proposed, though not yet confirmed. We developed an approach to study whether the expression of some CSC-associated markers is predictive of chemosensitivity in PDAC-derived cells. We established an independent set of 14 primary cultures, from PDXs obtained from patients with PDAC. The expressions of CD44, CD24, EpCAM and ALDH activity, all of which are CSC markers, were measured by flow cytometry analysis. Results are presented in Figure 4A. As shown, CD44 expression varied from 3.2 to 96.2%, CD24 from 0.5 to 45.3%, EpCAM from 0 to 94.2% and ALDH activity ranged from 0 to 74.5% in the PDX-derived cells (see Table S3). We then determined the IC50 for the 5 most commonly used drugs in the treatment of patients with PDAC, namely gemcitabine, 5FU, oxaliplatin, docetaxel (TXT) and SN-38 in these PDX-derived cells (Figure 4B and Figure S2) and analyzed its relationship with the expression of CSC markers. Importantly, no correlation was found between the sensitivity of the PDX-derived cells to each drug, and the amount of cells expressing CSC-associated markers individually or in combination (Figure 4C and Figure S3). We conclude that the number of cells expressing CSC markers in a population of cells derived from a PDX, does not predict its sensitivity to the more frequently used PDAC treatments.


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)

CSC-associated marker expression in vitro and its relationship to chemosensitivity(A) Flow cytometry was performed to identify quadruple staining for CD44-APC, EpCAM-VioBlue, CD24-PE and ALDH-FITC in fourteen primary cell-derived xenografts (n = 3). (B) Each cell line was treated with increasing concentrations (from 0 to 1000 μM) of Gemcitabine, Docetaxel (TXT), 5-Fluouracil (5FU), Oxaliplatin and the active metabolite of Irinotecan known as SN-38. The rate of cell survival was measured after 72 h of treatment. A sensitivity profile was obtained for each drug and the IC50 data is presented in the table. (C) Linear regression analysis to assess the level of expression of each CSC-associated marker and IC50 corresponding to each drug, was performed. N=3 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: CSC-associated marker expression in vitro and its relationship to chemosensitivity(A) Flow cytometry was performed to identify quadruple staining for CD44-APC, EpCAM-VioBlue, CD24-PE and ALDH-FITC in fourteen primary cell-derived xenografts (n = 3). (B) Each cell line was treated with increasing concentrations (from 0 to 1000 μM) of Gemcitabine, Docetaxel (TXT), 5-Fluouracil (5FU), Oxaliplatin and the active metabolite of Irinotecan known as SN-38. The rate of cell survival was measured after 72 h of treatment. A sensitivity profile was obtained for each drug and the IC50 data is presented in the table. (C) Linear regression analysis to assess the level of expression of each CSC-associated marker and IC50 corresponding to each drug, was performed. N=3 per group.
Mentions: The association between chemoresistance and CSC marker expression in vitro has been proposed, though not yet confirmed. We developed an approach to study whether the expression of some CSC-associated markers is predictive of chemosensitivity in PDAC-derived cells. We established an independent set of 14 primary cultures, from PDXs obtained from patients with PDAC. The expressions of CD44, CD24, EpCAM and ALDH activity, all of which are CSC markers, were measured by flow cytometry analysis. Results are presented in Figure 4A. As shown, CD44 expression varied from 3.2 to 96.2%, CD24 from 0.5 to 45.3%, EpCAM from 0 to 94.2% and ALDH activity ranged from 0 to 74.5% in the PDX-derived cells (see Table S3). We then determined the IC50 for the 5 most commonly used drugs in the treatment of patients with PDAC, namely gemcitabine, 5FU, oxaliplatin, docetaxel (TXT) and SN-38 in these PDX-derived cells (Figure 4B and Figure S2) and analyzed its relationship with the expression of CSC markers. Importantly, no correlation was found between the sensitivity of the PDX-derived cells to each drug, and the amount of cells expressing CSC-associated markers individually or in combination (Figure 4C and Figure S3). We conclude that the number of cells expressing CSC markers in a population of cells derived from a PDX, does not predict its sensitivity to the more frequently used PDAC treatments.

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