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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

Depletion of CD44 for PDAC relapse treatment(A) Gemcitabine treated tumors were transplanted into new mice and allowed to continue to grow (tumor-gem P1), and CD44 expression was evaluated by immunofluorescence and by western blot. (B) Quantification of CD44 expression is shown. (C) AO-IPC xenografts treated with vehicle or gemcitabine (100 mg/kg, biweekly, from days 35 to 85) were then treated with anti-CD44 mAb 200 μg/mice biweekly and tumor volume was monitored weekly (mm3). (D) AO-IPC xenografts were treated with vehicle or anti-CD44 (200 μg/mice biweekly) from days 35 to 85. Scale bar represents 100 μm. Error bars ± SEM; n=3 per group. *P<0.05, **P<0.001 compared to vehicle samples.
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Figure 6: Depletion of CD44 for PDAC relapse treatment(A) Gemcitabine treated tumors were transplanted into new mice and allowed to continue to grow (tumor-gem P1), and CD44 expression was evaluated by immunofluorescence and by western blot. (B) Quantification of CD44 expression is shown. (C) AO-IPC xenografts treated with vehicle or gemcitabine (100 mg/kg, biweekly, from days 35 to 85) were then treated with anti-CD44 mAb 200 μg/mice biweekly and tumor volume was monitored weekly (mm3). (D) AO-IPC xenografts were treated with vehicle or anti-CD44 (200 μg/mice biweekly) from days 35 to 85. Scale bar represents 100 μm. Error bars ± SEM; n=3 per group. *P<0.05, **P<0.001 compared to vehicle samples.

Mentions: CD44 is used in other cancers as an efficient therapeutic target [22]. Due to its increased expression in PDAC residual tumors, CD44 may be a viable therapeutic target to treat this disease. We therefore evaluated if, during long-term treatments with chemotherapeutic agents, CD44+ cells continued to accumulate. The PDXs were treated for one cycle of treatment with gemcitabine followed by transplantation of the relapsed tumors to other mice (Figure 6A). After sufficient tumor regrowth, we evaluated CD44 expression by immunofluorescence. We found that almost all cells were positive for CD44 staining, which indicated that relapsing tumors are composed mainly, if not exclusively, of CD44+ cells (Figure 6B). Consequently, because CD44 is highly expressed in relapsing PDACs, we evaluated the potential of using the anti-CD44 mAb to treat PDAC relapse in xenografts. Xenografts were transplanted to mice and treated by a cycle of gemcitabine as described in Figure 6A and mice bearing residual tumors were depleted of CD44 by systemic injection of the anti-CD44 mAb (200 μg/mice, twice weekly) in gemcitabine resistant-derived PDXs. As shown in Figure 6C, treatment with the anti-CD44 mAb significantly reduced tumor volume to the half (450 mm3 ± 6.2). However, when we injected the anti-CD44 antibody into mice bearing a gemcitabine-untreated PDX, almost no effect on tumor growth was found (Figure 6D) indicating the futility of targeting CD44 in primary non-residual tumors. Altogether, these data strongly suggest that relapsing PDACs are mainly formed from CD44+ cells, which could be a promising therapeutic target.


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)

Depletion of CD44 for PDAC relapse treatment(A) Gemcitabine treated tumors were transplanted into new mice and allowed to continue to grow (tumor-gem P1), and CD44 expression was evaluated by immunofluorescence and by western blot. (B) Quantification of CD44 expression is shown. (C) AO-IPC xenografts treated with vehicle or gemcitabine (100 mg/kg, biweekly, from days 35 to 85) were then treated with anti-CD44 mAb 200 μg/mice biweekly and tumor volume was monitored weekly (mm3). (D) AO-IPC xenografts were treated with vehicle or anti-CD44 (200 μg/mice biweekly) from days 35 to 85. Scale bar represents 100 μm. Error bars ± SEM; n=3 per group. *P<0.05, **P<0.001 compared to vehicle samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Depletion of CD44 for PDAC relapse treatment(A) Gemcitabine treated tumors were transplanted into new mice and allowed to continue to grow (tumor-gem P1), and CD44 expression was evaluated by immunofluorescence and by western blot. (B) Quantification of CD44 expression is shown. (C) AO-IPC xenografts treated with vehicle or gemcitabine (100 mg/kg, biweekly, from days 35 to 85) were then treated with anti-CD44 mAb 200 μg/mice biweekly and tumor volume was monitored weekly (mm3). (D) AO-IPC xenografts were treated with vehicle or anti-CD44 (200 μg/mice biweekly) from days 35 to 85. Scale bar represents 100 μm. Error bars ± SEM; n=3 per group. *P<0.05, **P<0.001 compared to vehicle samples.
Mentions: CD44 is used in other cancers as an efficient therapeutic target [22]. Due to its increased expression in PDAC residual tumors, CD44 may be a viable therapeutic target to treat this disease. We therefore evaluated if, during long-term treatments with chemotherapeutic agents, CD44+ cells continued to accumulate. The PDXs were treated for one cycle of treatment with gemcitabine followed by transplantation of the relapsed tumors to other mice (Figure 6A). After sufficient tumor regrowth, we evaluated CD44 expression by immunofluorescence. We found that almost all cells were positive for CD44 staining, which indicated that relapsing tumors are composed mainly, if not exclusively, of CD44+ cells (Figure 6B). Consequently, because CD44 is highly expressed in relapsing PDACs, we evaluated the potential of using the anti-CD44 mAb to treat PDAC relapse in xenografts. Xenografts were transplanted to mice and treated by a cycle of gemcitabine as described in Figure 6A and mice bearing residual tumors were depleted of CD44 by systemic injection of the anti-CD44 mAb (200 μg/mice, twice weekly) in gemcitabine resistant-derived PDXs. As shown in Figure 6C, treatment with the anti-CD44 mAb significantly reduced tumor volume to the half (450 mm3 ± 6.2). However, when we injected the anti-CD44 antibody into mice bearing a gemcitabine-untreated PDX, almost no effect on tumor growth was found (Figure 6D) indicating the futility of targeting CD44 in primary non-residual tumors. Altogether, these data strongly suggest that relapsing PDACs are mainly formed from CD44+ cells, which could be a promising therapeutic target.

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