Influence of Tumor Cell and Stroma Sensitivity on Tumor Response to Radiation

Ogawa, Kazuhiko; Boucher, Yves; Kashiwagi, Satoshi; Chen, David J.; Gerweck, Leo E.

doi:10.1158/0008-5472.can-06-4498

Cited by 54 publications

(36 citation statements)

References 20 publications

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“…Apart from the radiosensitivity of tumor cells as an important determinant of tumor response (44), the degree of radiation-induced microvascular destruction might contribute to tumor cell death (45)(46)(47)(48). Radiation-induced endothelial apoptosis starts at exposure to single-dose radiation of 8 to 10 Gy, being maximal at 20 to 25 Gy (45).…”

Section: Hif-1 and Vascular Radiosensitivitymentioning

confidence: 99%

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

Meijer

Kaanders

Span

et al. 2012

Clinical Cancer Research

384

344

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Radiotherapy, an important treatment modality in oncology, kills cells through induction of oxidative stress. However, malignant tumors vary in their response to irradiation as a consequence of resistance mechanisms taking place at the molecular level. It is important to understand these mechanisms of radioresistance, as counteracting them may improve the efficacy of radiotherapy. In this review, we describe how the hypoxia-inducible factor 1 (HIF-1) pathway has a profound effect on the response to radiotherapy. The main focus will be on HIF-1-controlled protection of the vasculature postirradiation and on HIF-1 regulation of glycolysis and the pentose phosphate pathway. This aberrant cellular metabolism increases the antioxidant capacity of tumors, thereby countering the oxidative stress caused by irradiation. From the results of translational studies and the first clinical phase I/II trials, it can be concluded that targeting HIF-1 and tumor glucose metabolism at several levels reduces the antioxidant capacity of tumors, affects the tumor microenvironment, and sensitizes various solid tumors to irradiation. Clin Cancer Res; 18(20); 5585-94. Ó2012 AACR.

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Section: Hif-1 and Vascular Radiosensitivitymentioning

confidence: 99%

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

Meijer

Kaanders

Span

et al. 2012

Clinical Cancer Research

384

344

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“…EGFR mutation status was determined by PCR amplification and sequence analysis of exons 18,19,20, and 21 comprising the tyrosine kinase domain. KRAS genotyping was assessed by PCR amplification and sequence analysis of exon 1 (codons 12 and 13) and exon 2 (codon 61).…”

Section: Patientsmentioning

confidence: 99%

“…Although protocol manipulations such as optimization of cell culture media or plating cell suspensions in agar may improve colony formation, many cell lines remain challenging for clonogenic survival analyses. Third, the complex interactions of tumor cells with surrounding stroma and normal tissues which can affect radiation responses (18,19) are not recapitulated with in vitro models.…”

Section: Introductionmentioning

confidence: 99%

A Clinical Model for Identifying Radiosensitive Tumor Genotypes in Non–Small Cell Lung Cancer

Johung

Yao

et al. 2013

Clinical Cancer Research

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Purpose: Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes.Experimental Design: Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments.Results: In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred infield (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFRmutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P ¼ 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment.Conclusions: This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.

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“…At first sight, it is difficult to understand how the large radiation doses given locally to brain tumors do not result in cures, because even though all of the tumor cells may not be sterilized by radiation, it is unlikely that any of the endothelial cells in the tumor could survive the large doses given. Indeed, recent data demonstrate that the response of tumors to irradiation can be affected by the sensitivity of tumor endothelial cells (5,6).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice

Kioi¹,

Vogel²,

Schultz³

et al. 2010

J. Clin. Invest.

714

689

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Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b + myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.

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Influence of Tumor Cell and Stroma Sensitivity on Tumor Response to Radiation

Abstract: In this study, we evaluated the role of tumor cell and tumor stroma sensitivity as determinants of radiation-induced tumor growth delay. A DNA double-strand break repair-defective DNA-PKcs À/À tumor cell line and its radioresistant DNAPKcs +/+

Cited by 54 publications

References 20 publications

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

Targeting Hypoxia, HIF-1, and Tumor Glucose Metabolism to Improve Radiotherapy Efficacy

A Clinical Model for Identifying Radiosensitive Tumor Genotypes in Non–Small Cell Lung Cancer

Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice

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