Limits...
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

Heterogeneous response to gemcitabine treatment(A) Mice bearing primary xenografts were treated with 100 mg/kg gemcitabine, and were measured weekly for changes in tumor volume. The length of the treatment is marked in gray. (B) Various histological features were detected by H&E staining of PDAC-vehicle treated tumors (upper panel) and gemcitabine-treated tumors (bottom panel). (C) PDXs Alcian Blue staining stains acid mucosubstances and acetic mucins. Scale bar represents 100 and 50 μm. Error bars ± SEM; n=3 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4480689&req=5

Figure 1: Heterogeneous response to gemcitabine treatment(A) Mice bearing primary xenografts were treated with 100 mg/kg gemcitabine, and were measured weekly for changes in tumor volume. The length of the treatment is marked in gray. (B) Various histological features were detected by H&E staining of PDAC-vehicle treated tumors (upper panel) and gemcitabine-treated tumors (bottom panel). (C) PDXs Alcian Blue staining stains acid mucosubstances and acetic mucins. Scale bar represents 100 and 50 μm. Error bars ± SEM; n=3 per group.

Mentions: Seven patient-derived xenografts (PDX) were selected for study. Clinical and histopathological characteristics of the patients and the PDAC tumors are presented in Supplemental Table S2 and Figure S1. As shown in Figure 1A, X-IPC and AH-IPC tumors were highly sensitive, while I-IPC and C-NOR tumors were moderately sensitive to therapy. Meanwhile AO-IPC, HN14 and R-IPC tumors were highly resistant to gemcitabine treatment as shown in Figure 1A. However, after treatment withdrawal, both moderately sensitive and sensitive PDXs, started to re-grow (Figure 1A). Surprisingly, histological analysis of the PDX tissues revealed that after treatment, all tumors presented with morphological features of improved differentiation, with a gain in glandular formation, a well polarized phenotype (see Figure 1B) and a strong production of mucus, as demonstrated by alcian blue staining (Figure 1C). These results allow us to conclude that following gemcitabine treatment, the PDAC tumor cell phenotype alters, to become more differentiated.


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)

Heterogeneous response to gemcitabine treatment(A) Mice bearing primary xenografts were treated with 100 mg/kg gemcitabine, and were measured weekly for changes in tumor volume. The length of the treatment is marked in gray. (B) Various histological features were detected by H&E staining of PDAC-vehicle treated tumors (upper panel) and gemcitabine-treated tumors (bottom panel). (C) PDXs Alcian Blue staining stains acid mucosubstances and acetic mucins. Scale bar represents 100 and 50 μm. Error bars ± SEM; n=3 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Heterogeneous response to gemcitabine treatment(A) Mice bearing primary xenografts were treated with 100 mg/kg gemcitabine, and were measured weekly for changes in tumor volume. The length of the treatment is marked in gray. (B) Various histological features were detected by H&E staining of PDAC-vehicle treated tumors (upper panel) and gemcitabine-treated tumors (bottom panel). (C) PDXs Alcian Blue staining stains acid mucosubstances and acetic mucins. Scale bar represents 100 and 50 μm. Error bars ± SEM; n=3 per group.
Mentions: Seven patient-derived xenografts (PDX) were selected for study. Clinical and histopathological characteristics of the patients and the PDAC tumors are presented in Supplemental Table S2 and Figure S1. As shown in Figure 1A, X-IPC and AH-IPC tumors were highly sensitive, while I-IPC and C-NOR tumors were moderately sensitive to therapy. Meanwhile AO-IPC, HN14 and R-IPC tumors were highly resistant to gemcitabine treatment as shown in Figure 1A. However, after treatment withdrawal, both moderately sensitive and sensitive PDXs, started to re-grow (Figure 1A). Surprisingly, histological analysis of the PDX tissues revealed that after treatment, all tumors presented with morphological features of improved differentiation, with a gain in glandular formation, a well polarized phenotype (see Figure 1B) and a strong production of mucus, as demonstrated by alcian blue staining (Figure 1C). These results allow us to conclude that following gemcitabine treatment, the PDAC tumor cell phenotype alters, to become more differentiated.

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