Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis

Inada, Masaki; Takita, Morichika; Yokoyama, S.; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

doi:10.1074/jbc.m115.669481

Cited by 35 publications

(20 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, injection of B16F10 melanoma cells into left ventricle resulted in macroscopically recognizable metastasis in bones, ovaries, adrenal glands, and brain at days 12-17 (Jones et al 2006). Our melanoma subline also exhibits a similar metastasis in systemic organs additionally including lungs, liver, and kidney but rarely in brain and muscle (Inada et al 2015). Taken together, if metastatic process includes primary tumor-led preselection or precultivation of the target organ or soil in the total absence of tumor cells or seed in the tissue, then this should be called premetastatic organ.…”

Section: Llc B16mentioning

confidence: 56%

Premetastasis

Maru

2019

Cold Spring Harb Perspect Med

Self Cite

View full text Add to dashboard Cite

Sterile inflammation within primary tumor tissues can spread to distant organs that are devoid of tumor cells. This happens in a manner dependent on tumor-led secretome, before the actual metastasis occurs. The premetastatic microenvironment is established in this way and is at least partly regulated by hijacking the host innate immune system. The biological manifestation of premetastasis include increased vascular permeability, cell mobilization via the blood stream, degradation of the extracellular matrix, immunosuppression, and host antineoplastic activities.

show abstract

Section: Llc B16mentioning

confidence: 56%

Premetastasis

Maru

2019

Cold Spring Harb Perspect Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Inada et al reported that the VEGF-A secretion from the CAFs within melanoma xenografts was enhanced by PGE2 and this enhancement was significantly suppressed by an EP4 antagonist, which suggest that PGE2-EP4 signaling plays an important role in the secretion of VEGF-A from CAFs [60].…”

Section: Fibroblastsmentioning

confidence: 99%

Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer

Mizuno

Kawada

Sakai

2019

IJMS

131

100

View full text Add to dashboard Cite

The number of colorectal cancer (CRC) patients is increasing worldwide. Accumulating evidence has shown that the tumor microenvironment (TME), including macrophages, neutrophils, and fibroblasts, plays an important role in the development and progression of CRC. Although targeting the TME could be a promising therapeutic approach, the mechanisms by which inflammatory cells promote CRC tumorigenesis are not well understood. When inflammation occurs in tissues, prostaglandin E2 (PGE2) is generated from arachidonic acid by the enzyme cyclooxygenase-2 (COX-2). PGE2 regulates multiple functions in various immune cells by binding to the downstream receptors EP1, EP2, EP3, and EP4, and plays an important role in the development of CRC. The current therapies targeting PGE2 using non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors have failed due to the global prostanoid suppression resulting in the severe adverse effects despite the fact they could prevent tumorigenesis. Therefore, therapies targeting the specific downstream molecules of PGE2 signaling could be a promising approach. This review highlights the role of each EP receptor in the TME of CRC tumorigenesis and their therapeutic potential.

show abstract

“…The BMD was calculated by dividing the bone mineral content of the measured area by the area. CT scanning of the tibiae and calvariae was performed using a microfocus x-ray CT system (R_mCT2; Rigaku and SMX-90T; Shimadzu), and three-dimensional microstructural image data were reconstructed using the software program as reported previously (17).…”

Section: Differentiation Of Bone Marrow Macrophages Into Pre-osteoclamentioning

confidence: 99%

“…They suggested the possible effectiveness of cabozantinib in both soft tissues and bone sites, but the modulation of bone remodeling by the kinase inhibitor has not been studied. In our previous studies using mouse malignant melanoma B16 and human breast cancer MDA231, we have shown that cell-cell interactions between cancer cells and host osteoblasts could induce RANKL expression in osteoblasts and elicit osteoclastic differentiation and severe bone destruction in the metastatic sites (17,18). We therefore decided to examine the effects of MET/VEGFR kinase inhibitors on host cells such as osteoblasts and osteoclasts to define the possible role of these kinases in the bone phenotype associated with prostate cancer.…”

mentioning

confidence: 99%

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

Watanabe¹,

Hirata²,

Tominari

et al. 2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The tyrosine kinase inhibitor TAS-115 that blocks VEGF receptor and hepatocyte growth factor receptor MET signaling exhibits antitumor properties in xenografts of human gastric carcinoma. In this study, we have evaluated the efficacy of TAS-115 in preventing prostate cancer metastasis to the bone and bone destruction using the PC3 cell line. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction and subsequent tumor growths were detected. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation by suppressing osteoclastic bone resorption. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption when co-cultured with calvarial bone, but TAS-115 effectively suppressed the PC3-induced bone destruction. We found that macrophage colony-stimulating factor-dependent macrophage differentiation and subsequent receptor activator of NF-B ligand-induced osteoclast formation were largely suppressed by adding TAS-115. The phosphorylation of the macrophage colony-stimulating factor receptor FMS and osteoclast related kinases such as ERK and Akt were also suppressed by the presence of TAS-115. Gene expression profiling showed that FMS expression was only seen in macrophage and in the osteoclast cell lineage. Our study indicates that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is critical for bone destruction induced by tumor cells and that targeting of MET/VEGF receptor/FMS activity makes it a promising therapeutic candidate for the treatment of prostate cancer patients with bone metastasis.VEGF signaling through the tyrosine kinase receptor VEGF receptor (VEGFR) 3 is a pivotal factor for tumor angiogenesis that regulates tumor progression. However, VEGFR-targeted inhibitor monotherapies showed limited effects on various carcinomas, and even combination therapies with chemotherapeutic agents are unsatisfactory (1, 2). The tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and HGF-MET signaling is also involved in tumor progression, metastasis, angiogenesis, and resistance to chemotherapy in various cancers, indicating that MET kinase inhibitors could have major therapeutic potential. Inhibition of both VEGFR and MET signaling pathways has been reported to suppress tumor growth and angiogenesis synergistically (3), suggesting the possibility that the dual inhibition of VEGFR and MET signals may have potential effects on the prevention of tumor growth. Recently, Fujita et al. (4) developed a novel VEGFR/MET-targeted tyrosine kinase inhibitor, TAS-115, and showed its antitumor properties in MET-amplified human cancer-bearing mice. In this study, we have investigated the effect of TAS-115 on prostate cancer cell metastasis to bone and a process associated with osteoclast activation.Bone remodeling is regulated by osteoclastic bone resorption and new bone formation. Osteoclasts, which are the primary bone-resorbing cells, are differentiated from macrophages b...

show abstract

Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis

Cited by 35 publications

References 43 publications

Premetastasis

Premetastasis

Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

Contact Info

Product

Resources

About