CXCR4/CXCL12 Mediate Autocrine Cell- Cycle Progression in NF1-Associated Malignant Peripheral Nerve Sheath Tumors

Mo, Wei; Chen, Jian; Patel, Aditi; Zhang, Liang; Chau, Vincent; Li, Yanjiao; Cho, Woo-Sung; Lim, Kyun; Xu, Jing; Lazar, Alexander J.; Creighton, Chad J.; Bolshakov, Svetlana; McKay, Renée M.; Lev, Dina; Le, Lu Q.; Parada, Luis F.

doi:10.1016/j.cell.2013.01.053

Cited by 134 publications

(136 citation statements)

References 55 publications

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“…As part of this effort, several laboratories have explored the possibility that aberrant growth factor signaling is a key upstream mediator of Ras activation in MPNSTs. These studies identified several growth factors and growth factor receptors that potentially contribute to neurofibroma and MPNST pathogenesis, including the epidermal growth factor (EGF) receptor, 24 neuregulin-1 (NRG1), 24 platelet-derived growth factor, 24 hepatocyte growth factor, and its c-Met receptor, 24 the insulin-like growth factor 1 receptor, 51 transforming growth factor-b1, 52 lysophosphatidic acid, 53 midkine, 52 Kit ligand and its c-Kit receptor, 24 CXCR4 and its CXCL12 ligand, 54 basic fibroblast growth factor, and vascular endothelial growth factor. 55 However, the strength of the evidence…”

Section: Genomic Abnormalities Mediating Neurofibroma-mpnst Progressionmentioning

confidence: 99%

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Carroll

2016

The American Journal of Pathology

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Comprehensive genomic analyses of common nervous system cancers provide new insights into their pathogenesis, diagnosis, and treatment. Although analogous studies of rare nervous system tumors are needed, there are major barriers to performing such studies. Cross-species comparative oncogenomics, identifying driver mutations in mouse cancer models and validating them in human tumors, is a promising alternative. Although still in its infancy, this approach is being applied to malignant peripheral nerve sheath tumors (MPNSTs), rare Schwann cellederived malignancies that occur sporadically, after radiotherapy, and in neurofibromatosis type 1. Studies of human neurofibromatosis type 1eassociated tumors suggest that NF1 tumor suppressor loss in Schwann cells triggers cell-autonomous and intercellular changes, resulting in development of benign neurofibromas; subsequent neurofibroma-MPNST progression is caused by aberrant growth factor signaling and mutations affecting the p16 INK4A -cyclin D1-CDK4-Rb and p19 ARF -Mdm2-p53 cell cycle pathways. Mice with Nf1, Trp53, and/or Cdkn2a mutations that overexpress the Schwann cell mitogen neuregulin-1 or overexpress the epidermal growth factor receptor validate observations in human tumors and, to various degrees, model human tumorigenesis. Genomic analyses of MPNSTs arising in neuregulin-1 and epidermal growth factor receptor-overexpressing mice and forward genetic screens with Sleeping Beauty transposons implicate additional signaling cascades in MPNST pathogenesis. These studies confirm the utility of mouse models for MPNST driver gene discovery and provide new insights into the complexity of MPNST pathogenesis. (Am J Pathol 2016, 186: 464e477; http://dx

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Section: Genomic Abnormalities Mediating Neurofibroma-mpnst Progressionmentioning

confidence: 99%

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Carroll

2016

The American Journal of Pathology

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“…Therefore, a CXCR4 antagonist with desirable in vivo pharmacologic and toxicologic properties would have potential for treatment of human cancers. Interruption of CXCR4 and SDF-1 axis has demonstrated antitumor growth activities in a variety of preclinical tumor models (2,3,(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Identification of LY2510924, a Novel Cyclic Peptide CXCR4 Antagonist That Exhibits Antitumor Activities in Solid Tumor and Breast Cancer Metastatic Models

Peng

Zhang

Paul

et al. 2015

Molecular Cancer Therapeutics

127

129

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Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC 50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC 50 value of 0.26 nmol/L and inhibited SDF-1/ CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer. Mol Cancer Ther; 14(2); 480-90. Ó2014 AACR.

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“…Tumor-secreted growth factors can affect tumor microenvironment (1,2), as well as stimulate the cancer cells themselves to proliferate and develop a more malignant phenotype in an autocrine manner (3)(4)(5)(6). A variety of growth factors and cytokines exert their effects on cancer cells by activating the membrane-associated phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, which regulates a wide spectrum of cellular functions, including proliferation, survival, angiogenesis, invasion, and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance—Implications for IGF-II and IGF-IR–Targeted Therapy

Tsao

Chan

et al. 2014

Clinical Cancer Research

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Purpose: To investigate the autocrine/endocrine role of Id1-induced insulin-like growth factor-II (IGF-II) in esophageal cancer, and evaluate the potential of IGF-II-and IGF-type I receptor (IGF-IR)-targeted therapies.Experimental Design: Antibody array-based screening was used to identify differentially secreted growth factors from Id1-overexpressing esophageal cancer cells. In vitro and in vivo assays were performed to confirm the induction of IGF-II by Id1, and to study the autocrine and endocrine effects of IGF-II in promoting esophageal cancer progression. Human esophageal cancer tissue microarray was analyzed for overexpression of IGF-II and its correlation with that of Id1 and phosphorylated AKT (p-AKT). The efficacy of intratumorally injected IGF-II antibody and intraperitoneally injected cixutumumab (fully human monoclonal IGF-IR antibody) was evaluated using in vivo tumor xenograft and experimental metastasis models.Results: Id1 overexpression induced IGF-II secretion, which promoted cancer cell proliferation, survival, and invasion by activating AKT in an autocrine manner. Overexpression of IGF-II was found in 21 of 35 (60%) esophageal cancer tissues and was associated with upregulation of Id1 and p-AKT. IGF-II secreted by Id1-overexpressing esophageal cancer xenograft could instigate the growth of distant esophageal tumors, as well as promote metastasis of circulating cancer cells. Targeting IGF-II and IGF-IR had significant suppressive effects on tumor growth and metastasis in mice. Cixutumumab treatment enhanced the chemosensitivity of tumor xenografts to fluorouracil and cisplatin.

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CXCR4/CXCL12 Mediate Autocrine Cell- Cycle Progression in NF1-Associated Malignant Peripheral Nerve Sheath Tumors

Cited by 134 publications

References 55 publications

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

Identification of LY2510924, a Novel Cyclic Peptide CXCR4 Antagonist That Exhibits Antitumor Activities in Solid Tumor and Breast Cancer Metastatic Models

Id1-Induced IGF-II and Its Autocrine/Endocrine Promotion of Esophageal Cancer Progression and Chemoresistance—Implications for IGF-II and IGF-IR–Targeted Therapy

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