Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells

Okamoto, Koichi; Tajima, Hidehiro; Ohta, Tetsuo; Nakanuma, Shinichi; Hayashi, Hironori; Nakagawara, Hisatoshi; Onishi, Ichiro; Takamura, Hiroyuki; Ninomiya, Itasu; Kitagawa, Hirohisa; Fushida, Sachio; Tani, Takashi; Fujimura, Takashi; Kayahara, Masato; Harada, Shinichi; Wakayama, Tomohiko; Iseki, Shoichi

doi:10.3892/ijo_00000776

Cited by 51 publications

(47 citation statements)

References 39 publications

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“…We have further suggested that circulating angiotensinogen in the blood is converted directly to Angiotensin II by trypsin in the tumor microenvironment at the weakly acidic pH found with anaerobic glycolysis [43]. We have also previously demonstrated that gastric cancer and intrahepatic cholangiocarcinoma tissue have higher levels of Angiotensin II than normal tissues [30,31]. Furthermore, gastric cancer tissue and cell lines alike have been found to express the AT1 receptor in both the current and previous studies [30,44].…”

Section: Discussionmentioning

confidence: 67%

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The Angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer

Okazaki¹,

Fushida²,

Harada³

et al. 2014

Cancer Letters

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Gastric cancer with peritoneal dissemination has poor clinical prognosis because of the presence of rich stromal fibrosis and acquired drug resistance. Recently, Angiotensin II type I receptor blockers such as candesartan have attracted attention for their potential anti-fibrotic activity. We examined whether candesartan could attenuate tumor proliferation and fibrosis through the interaction between gastric cancer cell line (MKN45) cells and human peritoneal mesothelial cells. Candesartan significantly reduced TGF-β1 expression and epithelial-to-mesenchymal transition-like change, while tumor proliferation and stromal fibrosis were impaired. Targeting the Angiotensin II signaling pathway may therefore be an efficient strategy for treatment of tumor proliferation and fibrosis.

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Section: Discussionmentioning

confidence: 67%

“…Previously, several studies have identified that Angiotensin II can promote cell proliferation during cancer development, and Angiotensin II type 1 (AT1) blockers (ARBs) may suppress this effect by antagonizing the AT1 receptor [30][31][32]. Furthermore, ARBs have recently attracted attention for their direct anti-fibrotic activity.…”

Section: Introductionmentioning

confidence: 99%

The Angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer

Okazaki¹,

Fushida²,

Harada³

et al. 2014

Cancer Letters

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“…In our previous study, we demonstrated that hepatic stellate cell (HSC) activation by angiotensin II (AngII) facilitated stromal fibrosis and tumor progression via an interaction with cancer cells in ICC tissues (6). Tumor progression and fibrosis are pivotal aspects of malignancy and several factors, including epidermal growth factor (EGF), transforming growth factor-β (TGF-β), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), trypsinogen, AngII, and chemokines including SDF-1, are regarded as possibly being involved in cross-talk in tumor-stromal interactions (2)(3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma

Okamoto

Tajima

Nakanuma

et al. 2012

International Journal of Oncology

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We previously reported that hepatic stellate cells (HSCs) activated by angiotensin II (AngII) facilitate stromal fibrosis and tumor progression in intrahepatic cholangiocarcinoma (ICC). AngII has been known as a growth factor which can promote epithelial-to-mesenchymal transition (EMT) in renal epithelial cells, alveolar epithelial cells and peritoneal mesothelial cells. However, in the past, the relationship between AngII and stromal cell-derived factor-1 (SDF-1) in the microenvironment around cancer and the role of AngII on EMT of cancer cells has not been reported in detail. SDF-1 and its specific receptor, CXCR4, are now receiving attention as a mechanism of cell progression and metastasis. In this study, we examined whether activated HSCs promote tumor fibrogenesis, tumor progression and distant metastasis by mediating EMT via the AngII/AngII type 1 receptor (AT-1) and the SDF-1/CXCR4 axis. Two human ICC cell lines and a human HSC line, LI-90, express CXCR4. Significantly higher concentration of SDF-1α was released into the supernatant of LI-90 cells to which AngII had been added. SDF-1α increased the proliferative activity of HSCs and enhanced the activation of HSCs as a growth factor. Furthermore, addition of SDF-1α and AngII enhanced the increase of the migratory capability and vimentin expression, reduced E-cadherin expression, and translocated the expression of β-catenin into the nucleus and cytoplasm in ICC cells. Co-culture with HSCs also enhanced the migratory capability of ICC cells. These findings suggest that SDF-1α, released from activated HSCs and AngII, play important roles in cancer progression, tumor fibrogenesis, and migration in autocrine and paracrine fashion by mediating EMT. Our mechanistic findings may provide pivotal insights into the molecular mechanism of the AngII and SDF-1α-initiated signaling pathway that regulates fibrogenesis in cancerous stroma, tumor progression and meta-stasis of tumor cells expressing AT-1 and CXCR4.

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“…This altered stroma has been implicated in cancer development and maintenance, and also in the poor sensitivity of pancreatic cancer to chemotherapeutics. Furthermore, the interaction between carcinoma cells and stromal cells, including CAFs, influence stromal formation, invasion and metastasis (60,61).…”

Section: Effect Of Preoperative Therapy On Pancreatic Cancer Tissuesmentioning

confidence: 99%

“…Therefore, treatments that inhibit TGF-β are important in antitumor immunity (99). Metformin (100,101) and ARB (61,78,102) are well-known as drugs that inhibit TGF-β, in addition to inhibition of EMT. Although clinical effectiveness is unlikely to be achieved using one of these as an anticancer agent, it is reasonable to use these drugs for patients with comorbidities, including diabetes, hypertension and hyperlipidemia, in the treatment of pancreatic cancer.…”

Section: Effect Of Preoperative Therapy On Pancreatic Cancer Tissuesmentioning

confidence: 99%

Neoadjuvant chemotherapy for pancreatic cancer: Effects on cancer tissue and novel perspectives

et al. 2017

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Abstract. Chemotherapy for pancreatic cancer has diversified following the addition of more treatment regimens; however, in spite of this, pancreatic cancer remains a fatal disease. Preoperative (neoadjuvant) chemotherapy (NAC) or neoadjuvant chemoradiation therapy (NACRT) has been developed and implemented. For patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), a number of clinical trials have been conducted; NACRT was demonstrated to improve resectability, R0 resection rate, overall survival rate, disease-free survival rate and even an LAPC and BRPC survival advantage over NAC. However, from the knowledge obtained from resected specimens following preoperative treatment, residual pancreatic cancer tissues following NAC are rich in chemoresistant cancer stem-like cells and epithelial-mesenchymal transition (EMT) markers. Conversely, metformin, angiotensin receptor blocker, statins and low-dose paclitaxel are well-known as drugs that inhibit EMT, which is associated with cancer stem cell-like characteristics. Although clinical effectiveness is unlikely to be achieved using one of these as an anticancer agent, it is reasonable to use these drugs for patients with comorbidities in the treatment of pancreatic cancer. Furthermore, gemcitabine (GEM) affects antitumor immunity by stimulating the expression of major histocompatibility complex class I-related chain A on the surface of cancer cells to enhance the cytotoxicity of natural killer cells. Considering EMT and antitumor immunity, there is a possibility that GEM and nanoparticle albumin-bound paclitaxel therapy is the most suitable regimen for treating pancreatic cancer. However, even as preoperative treatment progresses, R0 resection is the most important factor for the long-term survival of pancreatic cancer patients.

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Angiotensin II induces tumor progression and fibrosis in intrahepatic cholangiocarcinoma through an interaction with hepatic stellate cells

Cited by 51 publications

References 39 publications

The Angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer

The Angiotensin II type 1 receptor blocker candesartan suppresses proliferation and fibrosis in gastric cancer

Angiotensin II enhances epithelial-to-mesenchymal transition through the interaction between activated hepatic stellate cells and the stromal cell-derived factor-1/CXCR4 axis in intrahepatic cholangiocarcinoma

Neoadjuvant chemotherapy for pancreatic cancer: Effects on cancer tissue and novel perspectives

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