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Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

Suzuki M, Chiwaki F, Sawada Y, Ashikawa M, Aoyagi K, Fujita T, Yanagihara K, Komatsu M, Narita M, Suzuki T, Nagase H, Kushima R, Sakamoto H, Fukagawa T, Katai H, Nakagama H, Yoshida T, Uezono Y, Sasaki H - PLoS ONE (2015)

Bottom Line: We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs).The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc.These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT
The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

No MeSH data available.


Related in: MedlinePlus

PENK encoding opioid growth factor (OGF) is preferentially expressed in diffuse-type gastric cancers (GCs).Representative histological image (hematoxylin-eosin, HE) and Ki-67 immunostaining of diffuse-type GC (A) and intestinal-type GC (B). Scale bar, 50 μm. C, supervised clustering analysis of 892 specifically expressed genes in 12 diffuse-type and 18 intestinal-type GCs. By the Wilcoxon u-test (p<0.05) and a 2-fold change, 188 genes were selected as specific genes for 18 intestinal-type GCs, and 704 genes were selected as specific genes for 12 diffuse-type GCs. The results of a two-dimensional hierarchical clustering analysis of the 892 selected genes are shown. D, RT-PCR analyses of OGF signaling molecules, PENK and its receptor OGFR, in diffuse-type and intestinal-type GCs.
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pone.0123407.g001: PENK encoding opioid growth factor (OGF) is preferentially expressed in diffuse-type gastric cancers (GCs).Representative histological image (hematoxylin-eosin, HE) and Ki-67 immunostaining of diffuse-type GC (A) and intestinal-type GC (B). Scale bar, 50 μm. C, supervised clustering analysis of 892 specifically expressed genes in 12 diffuse-type and 18 intestinal-type GCs. By the Wilcoxon u-test (p<0.05) and a 2-fold change, 188 genes were selected as specific genes for 18 intestinal-type GCs, and 704 genes were selected as specific genes for 12 diffuse-type GCs. The results of a two-dimensional hierarchical clustering analysis of the 892 selected genes are shown. D, RT-PCR analyses of OGF signaling molecules, PENK and its receptor OGFR, in diffuse-type and intestinal-type GCs.

Mentions: Solid tumors with diffuse growth are composed of many myofibroblasts and few vessels (e.g., pancreatic cancers and scirrhous type of breast cancer) (S1 Fig). Depending on the conditions related to the microenvironment, such as nutrient deficiency, these tumors show a high prevalence of rarely-proliferative tumor cells. In support of these reports, diffuse-type GC shows a high proportion of Ki-67-negative non-proliferating tumor cells compared to intestinal-type GC (Fig 1A and 1B). We previously established a highly peritoneal metastatic cell line 60As6 by the 6-times transplantation of a diffuse-type GC-derived parental cell line (HSC-60) into a mouse peritoneal cavity [10]. We found that 60As6 cells exhibit apparent resistance to Doc by inducing growth arrest in G1 phase under serum starvation (S2A–S2C Fig), suggesting that the acquisition of this characteristic might be attributed to a particular tumor microenvironment, such as hyponutrition. To address the molecular mechanisms of dormancy related to chemoresistance of diffuse-type GC, we first searched for cell growth-suppressive signal pathways by a comparative gene expression analysis between 12 primary diffuse-type and 18 intestinal-type GCs (Fig 1C). In most of the intestinal-type GCs, CDC6, which is a typical marker of S-phase progression in the cell cycle, was highly expressed (S3A Fig). On the other hand, PENK encoding OGF was identified to be over-expressed in diffuse-type GCs (Fig 1C). PENK mRNA was also confirmed to be preferentially expressed in diffuse-type GCs compared with intestinal-type GCs by RT-PCR (Fig 1D). An increase in OGF secretion in cancer-associated ascites, but not peritoneal washings, was confirmed by ELISA (S3B Fig). Consistent with the expression profile of primary GCs, PENK and OGFR were expressed in the diffuse-type GC cell line HSC-60, 60As6 cells, and their mouse xenografts (60As6 xeno), whereas the intestinal-type GC cell line HSC-42 expressed only OGFR mRNA (Fig 2A). OGF has been reported to bind to two membrane receptors, μ- and δ-opioid receptors (OPRM1 and OPRD1, respectively), as well as to the nuclear receptor OGFR. Quite low expression of OPRM1 and OPRD1 was detected in both HSC-60 and 60As6 cells (S4A Fig). In various diffuse-type GC cell lines, little or no expression of these two membrane receptors was detected by RT-PCR (data not shown), whereas high expression levels of both PENK and OGFR were found in most of these cell lines (Fig S4B).


Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

Suzuki M, Chiwaki F, Sawada Y, Ashikawa M, Aoyagi K, Fujita T, Yanagihara K, Komatsu M, Narita M, Suzuki T, Nagase H, Kushima R, Sakamoto H, Fukagawa T, Katai H, Nakagama H, Yoshida T, Uezono Y, Sasaki H - PLoS ONE (2015)

PENK encoding opioid growth factor (OGF) is preferentially expressed in diffuse-type gastric cancers (GCs).Representative histological image (hematoxylin-eosin, HE) and Ki-67 immunostaining of diffuse-type GC (A) and intestinal-type GC (B). Scale bar, 50 μm. C, supervised clustering analysis of 892 specifically expressed genes in 12 diffuse-type and 18 intestinal-type GCs. By the Wilcoxon u-test (p<0.05) and a 2-fold change, 188 genes were selected as specific genes for 18 intestinal-type GCs, and 704 genes were selected as specific genes for 12 diffuse-type GCs. The results of a two-dimensional hierarchical clustering analysis of the 892 selected genes are shown. D, RT-PCR analyses of OGF signaling molecules, PENK and its receptor OGFR, in diffuse-type and intestinal-type GCs.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4390307&req=5

pone.0123407.g001: PENK encoding opioid growth factor (OGF) is preferentially expressed in diffuse-type gastric cancers (GCs).Representative histological image (hematoxylin-eosin, HE) and Ki-67 immunostaining of diffuse-type GC (A) and intestinal-type GC (B). Scale bar, 50 μm. C, supervised clustering analysis of 892 specifically expressed genes in 12 diffuse-type and 18 intestinal-type GCs. By the Wilcoxon u-test (p<0.05) and a 2-fold change, 188 genes were selected as specific genes for 18 intestinal-type GCs, and 704 genes were selected as specific genes for 12 diffuse-type GCs. The results of a two-dimensional hierarchical clustering analysis of the 892 selected genes are shown. D, RT-PCR analyses of OGF signaling molecules, PENK and its receptor OGFR, in diffuse-type and intestinal-type GCs.
Mentions: Solid tumors with diffuse growth are composed of many myofibroblasts and few vessels (e.g., pancreatic cancers and scirrhous type of breast cancer) (S1 Fig). Depending on the conditions related to the microenvironment, such as nutrient deficiency, these tumors show a high prevalence of rarely-proliferative tumor cells. In support of these reports, diffuse-type GC shows a high proportion of Ki-67-negative non-proliferating tumor cells compared to intestinal-type GC (Fig 1A and 1B). We previously established a highly peritoneal metastatic cell line 60As6 by the 6-times transplantation of a diffuse-type GC-derived parental cell line (HSC-60) into a mouse peritoneal cavity [10]. We found that 60As6 cells exhibit apparent resistance to Doc by inducing growth arrest in G1 phase under serum starvation (S2A–S2C Fig), suggesting that the acquisition of this characteristic might be attributed to a particular tumor microenvironment, such as hyponutrition. To address the molecular mechanisms of dormancy related to chemoresistance of diffuse-type GC, we first searched for cell growth-suppressive signal pathways by a comparative gene expression analysis between 12 primary diffuse-type and 18 intestinal-type GCs (Fig 1C). In most of the intestinal-type GCs, CDC6, which is a typical marker of S-phase progression in the cell cycle, was highly expressed (S3A Fig). On the other hand, PENK encoding OGF was identified to be over-expressed in diffuse-type GCs (Fig 1C). PENK mRNA was also confirmed to be preferentially expressed in diffuse-type GCs compared with intestinal-type GCs by RT-PCR (Fig 1D). An increase in OGF secretion in cancer-associated ascites, but not peritoneal washings, was confirmed by ELISA (S3B Fig). Consistent with the expression profile of primary GCs, PENK and OGFR were expressed in the diffuse-type GC cell line HSC-60, 60As6 cells, and their mouse xenografts (60As6 xeno), whereas the intestinal-type GC cell line HSC-42 expressed only OGFR mRNA (Fig 2A). OGF has been reported to bind to two membrane receptors, μ- and δ-opioid receptors (OPRM1 and OPRD1, respectively), as well as to the nuclear receptor OGFR. Quite low expression of OPRM1 and OPRD1 was detected in both HSC-60 and 60As6 cells (S4A Fig). In various diffuse-type GC cell lines, little or no expression of these two membrane receptors was detected by RT-PCR (data not shown), whereas high expression levels of both PENK and OGFR were found in most of these cell lines (Fig S4B).

Bottom Line: We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs).The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc.These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.

ABSTRACT
The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX) enhances the effect of docetaxel (Doc) by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF) and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs). The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

No MeSH data available.


Related in: MedlinePlus