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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

Schematic representation of the proposed model
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Figure 8: Schematic representation of the proposed model

Mentions: A sensitive tumor probably predominately consists of drug sensitive cells, whereas a resistant tumor is formed chiefly of resistant cells. This is known as the intra-tumor heterogeneity [38, 39]. Also, a tumor could be resistant to one particular drug, but sensitive to another. This is why a tumor may initially reduce in volume after first-line therapy and then progress and ultimately cause patient death. Regarding CD44+ cell accumulation, our findings showed that this increase occurs in both gemcitabine-resistant and sensitive tumors, probably due to clonal selection, which also includes CD44+ cells, as mentioned above. In this study, we observed that following gemcitabine treatments, the heterogeneous population of CD44+ cells is therapy-resistant, and has unique characteristics such as loss of the expression of the EMT marker ZEB1 and increased expression of the differentiation marker MUC1, along with elevated mucus production and a dramatic gain of differentiation characteristics. In addition, these CD44+ relapsing cells have the capacity to proliferate, suggesting that these cells generate a relapsing tumor, with a more differentiated phenotype (Figure 8). The fact that relapsing tumors present biological characteristics of differentiation is not surprising, as in cases of small-cell lung cancer, which become resistant to chemotherapy, an increased expression of differentiation markers has previously been reported [20, 21, 40-42]. Finally, to evaluate if this is a gemcitabine-dependent mechanism, we quantified CD44+ cells in docetaxel-treated tumors and we found a very close response to gemcitabine-treated xenografts, suggesting that this mechanism is not exclusively associated to the gemcitabine treatment.


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)

Schematic representation of the proposed model
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Schematic representation of the proposed model
Mentions: A sensitive tumor probably predominately consists of drug sensitive cells, whereas a resistant tumor is formed chiefly of resistant cells. This is known as the intra-tumor heterogeneity [38, 39]. Also, a tumor could be resistant to one particular drug, but sensitive to another. This is why a tumor may initially reduce in volume after first-line therapy and then progress and ultimately cause patient death. Regarding CD44+ cell accumulation, our findings showed that this increase occurs in both gemcitabine-resistant and sensitive tumors, probably due to clonal selection, which also includes CD44+ cells, as mentioned above. In this study, we observed that following gemcitabine treatments, the heterogeneous population of CD44+ cells is therapy-resistant, and has unique characteristics such as loss of the expression of the EMT marker ZEB1 and increased expression of the differentiation marker MUC1, along with elevated mucus production and a dramatic gain of differentiation characteristics. In addition, these CD44+ relapsing cells have the capacity to proliferate, suggesting that these cells generate a relapsing tumor, with a more differentiated phenotype (Figure 8). The fact that relapsing tumors present biological characteristics of differentiation is not surprising, as in cases of small-cell lung cancer, which become resistant to chemotherapy, an increased expression of differentiation markers has previously been reported [20, 21, 40-42]. Finally, to evaluate if this is a gemcitabine-dependent mechanism, we quantified CD44+ cells in docetaxel-treated tumors and we found a very close response to gemcitabine-treated xenografts, suggesting that this mechanism is not exclusively associated to the gemcitabine treatment.

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