Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis
Abstract Background Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no stud...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-019-1226-8 |
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| author | Zilong Yan Kenoki Ohuchida Shuang Fei Biao Zheng Weiyu Guan Haimin Feng Shin Kibe Yohei Ando Kazuhiro Koikawa Toshiya Abe Chika Iwamoto Koji Shindo Taiki Moriyama Kohei Nakata Yoshihiro Miyasaka Takao Ohtsuka Kazuhiro Mizumoto Makoto Hashizume Masafumi Nakamura |
| author_facet | Zilong Yan Kenoki Ohuchida Shuang Fei Biao Zheng Weiyu Guan Haimin Feng Shin Kibe Yohei Ando Kazuhiro Koikawa Toshiya Abe Chika Iwamoto Koji Shindo Taiki Moriyama Kohei Nakata Yoshihiro Miyasaka Takao Ohtsuka Kazuhiro Mizumoto Makoto Hashizume Masafumi Nakamura |
| author_sort | Zilong Yan |
| collection | DOAJ |
| description | Abstract Background Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer–stromal interaction. Methods Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor. Results Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer–stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model. Conclusions These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis. |
| first_indexed | 2024-12-10T11:50:56Z |
| format | Article |
| id | doaj.art-ada68f8dfc324664bd43f09899b3c368 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T11:50:56Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-ada68f8dfc324664bd43f09899b3c3682022-12-22T01:49:56ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-05-0138111610.1186/s13046-019-1226-8Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasisZilong Yan0Kenoki Ohuchida1Shuang Fei2Biao Zheng3Weiyu Guan4Haimin Feng5Shin Kibe6Yohei Ando7Kazuhiro Koikawa8Toshiya Abe9Chika Iwamoto10Koji Shindo11Taiki Moriyama12Kohei Nakata13Yoshihiro Miyasaka14Takao Ohtsuka15Kazuhiro Mizumoto16Makoto Hashizume17Masafumi Nakamura18Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityCancer Center of Kyushu University HospitalDepartment of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu UniversityDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu UniversityAbstract Background Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer–stromal interaction. Methods Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor. Results Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer–stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model. Conclusions These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis.http://link.springer.com/article/10.1186/s13046-019-1226-8ERK1/2Pancreatic cancerCancer–stromal interactionPancreatic stellate cellCellular senescence |
| spellingShingle | Zilong Yan Kenoki Ohuchida Shuang Fei Biao Zheng Weiyu Guan Haimin Feng Shin Kibe Yohei Ando Kazuhiro Koikawa Toshiya Abe Chika Iwamoto Koji Shindo Taiki Moriyama Kohei Nakata Yoshihiro Miyasaka Takao Ohtsuka Kazuhiro Mizumoto Makoto Hashizume Masafumi Nakamura Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis Journal of Experimental & Clinical Cancer Research ERK1/2 Pancreatic cancer Cancer–stromal interaction Pancreatic stellate cell Cellular senescence |
| title | Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis |
| title_full | Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis |
| title_fullStr | Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis |
| title_full_unstemmed | Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis |
| title_short | Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis |
| title_sort | inhibition of erk1 2 in cancer associated pancreatic stellate cells suppresses cancer stromal interaction and metastasis |
| topic | ERK1/2 Pancreatic cancer Cancer–stromal interaction Pancreatic stellate cell Cellular senescence |
| url | http://link.springer.com/article/10.1186/s13046-019-1226-8 |
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