Inhibition of Multidrug Transporter in Tumor Endothelial Cells Enhances Antiangiogenic Effects of Low-Dose Metronomic Paclitaxel

Akiyama, Kosuke; Maishi, Nako; Ohga, Noritaka; Hida, Yasuhiro; Ohba, Yusuke; Alam, Mohammad Towfik; Kawamoto, Taisuke; Ohmura, Hitomi; Yamada, Kenji; Torii, Chisaho; Shindoh, Masanobu

doi:10.1016/j.ajpath.2014.10.017

Cited by 32 publications

(39 citation statements)

References 35 publications

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“…We purchased 7‐week‐old female nude mice (BALB/c AJcl‐nu/nu) from CLEA Japan and housed them under specific pathogen‐free conditions. To visualize metastases to lungs, we used IVIS Spectrum (Caliper Life Science, Hopkinton, MA), Rluc‐expressing A375SM cells . We injected Rluc‐transfected A375SM (1 × 10 6 cells) subcutaneously into the right flanks of nude mice.…”

Section: Methodsmentioning

confidence: 99%

CXCL12–CXCR7 axis is important for tumor endothelial cell angiogenic property

Yamada

Maishi

Akiyama

et al. 2015

Intl Journal of Cancer

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We reported that tumor endothelial cells (TECs) differ from normal endothelial cells (NECs) in many aspects, such as gene expression profiles. Although CXCR7 is reportedly highly expressed in blood vessels of several tumors, its function in TECs is still unknown. To investigate this role, we isolated TECs from mouse tumor A375SM xenografts, and compared them with NECs from normal mouse dermis. After confirming CXCR7 upregulation in TECs, we analyzed its function using CXCR7 siRNA and CXCR7 inhibitor; CCX771. CXCR7 siRNA and CCX771 inhibited migration, tube formation and resistance to serum starvation in TECs but not in NECs. ERK1/2 phosphorylation was inhibited by CXCR7 knockdown in TECs. These results suggest that CXCR7 promotes angiogenesis in TECs via ERK1/2 phosphorylation. Using ELISA, we also detected CXCL12, a ligand of CXCR7, in conditioned medium from TECs, but not from NECs. CXCL12 neutralizing antibody significantly inhibited TEC random motility. VEGF stimulation upregulated CXCR7 expression in NECs, implying that VEGF mediates CXCR7 expression in endothelial cells. A CXCR7 inhibitor, CCX771 also inhibited tumor growth, lung metastasis and tumor angiogenesis in vivo. Taken together, the CXCL12-CXCR7 autocrine loop affects TEC proangiogenic properties, and could be the basis for an antiangiogenic therapy that specifically targets tumor blood vessels rather than normal vessels.Tumor growth and metastasis rely on angiogenesis. Tumor blood vessels deliver oxygen and nutrition to cancer cells and provide routes for them to metastasize.1 Antiangiogenic therapy using VEGF neutralization antibody and tyrosine kinase inhibitor has been shown to improve colon cancer survival rates.2 However, VEGF is also critical to survival of normal endothelial cells (NECs), in which its inhibition can cause several side effects, such as hypertension and bleeding.3 Therefore, identifying molecules that are specific for tumor blood endothelial cells (TECs) is important for development of antiangiogenic therapy that specifically targets tumor blood vessels, and would be safer than current drugs.We previously found several molecules that were more highly expressed in TECs than NECs. 4,5 We also reported that expression of C-X-C chemokine receptor type 7 (CXCR7) was upregulated in TECs of human renal carcinoma compared to NECs.6 CXCR7 is a G-protein-coupled chemokine receptor and its ligands are CXCL12 and CXCL11. CXCL12 affects embryonic cardiovascular formation. 7 Reportedly, CXCR7 mediates tumor proliferation and metastasis by binding to CXCL12 in various cancer cells. [8][9][10]

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Section: Methodsmentioning

confidence: 99%

CXCL12–CXCR7 axis is important for tumor endothelial cell angiogenic property

Yamada

Maishi

Akiyama

et al. 2015

Intl Journal of Cancer

Self Cite

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“…The ABC transporter family of proteins is also well characterized for its ability to efflux a wide range of small molecules and drugs. It was also reported that tumor ECs are resistant to low-dose chemotherapy through expression of ABCB1 (33). Therefore, to clarify the mechanism responsible for this differential sensitivity to antiangiogenic drugs, we investigated the expression of mRNA for the ABC drug transporters.…”

Section: Ec-sp Cells Are Resistant To Antiangiogenic Therapymentioning

confidence: 99%

Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance

et al. 2016

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Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor-like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo. These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor-like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance.

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“…The high expression of P-gp in many types of cancer tissues was reported to be correlated with a more aggressive phenotype [3,4,7,11,13,14]. In addition to being a drug transporter, in vitro studies also demonstrated additional functions of P-gp, such as for apoptosis and proliferation [5], cancer stem cells [5,17,18], angiogenesis [15,16], cell invasion and metastasis [19,20,21,22], which are critical for cancer initiation and progression. Previous studies have suggested that P-gp exerts its tumor-promoting function through protein–protein interaction [7,20,23].…”

Section: Discussionmentioning

confidence: 99%

“…Upregulated P-gp expression in cancer tissues is usually associated with a more malignant phenotype and poor clinical outcome for cancer patients [3,4,7,11,13,14]. Moreover, P-gp activity was associated with angiogenesis [15,16], cancer stem cells [5,17,18], cell migration and invasion [7,19,20,21,22], which are essential for carcinogenesis and cancer progression. These findings suggest that upregulated P-gp may confer enhanced cell invasion ability in drug-resistant cells.…”

Section: Introductionmentioning

confidence: 99%

Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells

Yang

Wang

et al. 2016

IJMS

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The emergence of multidrug resistance is always associated with more rapid tumor recurrence and metastasis. P-glycoprotein (P-gp), which is a well-known multidrug-efflux transporter, confers enhanced invasion ability in drug-resistant cells. Previous studies have shown that P-gp probably exerts its tumor-promoting function via protein-protein interaction. These interactions were implicated in the activation of intracellular signal transduction. We previously showed that P-gp binds to Anxa2 and promotes the invasiveness of multidrug-resistant (MDR) breast cancer cells through regulation of Anxa2 phosphorylation. However, the accurate mechanism remains unclear. In the present study, a co-immunoprecipitation coupled with liquid chromatography tandem mass spectrometry-based interactomic approach was performed to screen P-gp binding proteins. We identified Rack1 as a novel P-gp binding protein. Knockdown of Rack1 significantly inhibited proliferation and invasion of MDR cancer cells. Mechanistic studies demonstrated that Rack1 functioned as a scaffold protein that mediated the binding of P-gp to Anxa2 and Src. We showed that Rack1 regulated P-gp activity, which was necessary for adriamycin-induced P-gp-mediated phosphorylation of Anxa2 and Erk1/2. Overall, the findings in this study augment novel insights to the understanding of the mechanism employed by P-gp for promoting migration and invasion of MDR cancer cells.

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Inhibition of Multidrug Transporter in Tumor Endothelial Cells Enhances Antiangiogenic Effects of Low-Dose Metronomic Paclitaxel

Cited by 32 publications

References 35 publications

CXCL12–CXCR7 axis is important for tumor endothelial cell angiogenic property

CXCL12–CXCR7 axis is important for tumor endothelial cell angiogenic property

Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance

Rack1 Mediates the Interaction of P-Glycoprotein with Anxa2 and Regulates Migration and Invasion of Multidrug-Resistant Breast Cancer Cells

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