targeted-selective-treatment-pluripotent-stem-cell-derived-teratomas

Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model

The growing number of victims of &#34;stem cell tourism,&#34; the unregulated transplantation of stem cells worldwide, has raised concerns about the ...

Stanford University School of Medicine

Recently it has been observed in preclinical models that that radiation enhances the recruitment of circulating tumor cells to primary tumors, and results in tumor regrowth after treatment. This process may have implications for clinical radiotherapy, which improves control of a number of tumor types but which, despite continued dose escalation and aggressive fractionation, is unable to fully prevent local recurrences. By irradiating a single tumor within an animal bearing multiple lesions, we observed an increase in tumor cell migration to irradiated and unirradiated sites, suggesting a systemic component to this process. Previous work has identified the cytokine GM-CSF, produced by tumor cells following irradiation, as a key effector of this process. We evaluated the ability of systemic injections of a PEGylated form of GM-CSF to stimulate tumor cell migration. While increases in invasion and migration were observed for tumor cells in a transwell assay, we found that daily injections of PEG-GM-CSF to tumor-bearing animals did not increase migration of cells to tumors, despite the anticipated changes in circulating levels of granulocytes and monocytes produced by this treatment. Combination of PEG-GM-CSF treatment with radiation also did not increase tumor cell migration. These findings suggest that clinical use of GM-CSF to treat neutropenia in cancer patients will not have negative effects on the aggressiveness of residual cancer cells. However, further work is needed to characterize the mechanism by which GM-CSF facilitates systemic recruitment of trafficking tumor cells to tumors.

The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration.

Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in patients with TNBC, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared with nonrecurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8 T cells. Macrophages (CD11bF480) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of patients with TNBC. This study establishes the importance of macrophages in driving tumor cell recruitment to sites of local radiation therapy and suggests that this mechanism contributes to local recurrence in women with TNBC that are also immunosuppressed. http://cancerres.aacrjournals.org/content/canres/78/15/4241/F1.large.jpg .

Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients.

Translational research aims to provide direct support for advancing novel treatment approaches in oncology towards improving patient outcomes. Preclinical studies have a central role in this process and the ability to accurately model biological and physical aspects of the clinical scenario in radiation oncology is critical to translational success. The use of small animal irradiators with disease relevant mouse models and advanced in vivo imaging approaches offers unique possibilities to interrogate the radiotherapy response of tumors and normal tissues with high potential to translate to improvements in clinical outcomes. The present review highlights the current technology and applications of small animal irradiators, and explores how these can be combined with molecular and functional imaging in advanced preclinical radiotherapy research.

Edward Graves

Department of Pathology,
Department of Radiology,
Molecular Imaging Program,
Department of Radiation Oncology,
Department of Radiology, Molecular Imaging Program

Stanford University School of Medicine

Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model

Edward Graves

Department of Pathology,Department of Radiology,Molecular Imaging Program,Department of Radiation Oncology,Department of Radiology, Molecular Imaging Program

Stanford University School of Medicine

Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model

Department of Pathology,
Department of Radiology,
Molecular Imaging Program,
Department of Radiation Oncology,
Department of Radiology, Molecular Imaging Program