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Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model.

ABSTRACT: Tumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer xenograft mouse tumor model to investigate the spread of malignant cells during different treatments modalities.The biological data gained during these experiments were fed into our previously developed computer model "Cancer and Treatment Simulation Tool" (CaTSiT) to model the growth of the primary tumor, its metastatic deposit and also the influence on different therapies. Furthermore, we performed quantitative histology analyses to verify our predictions in xenograft mouse tumor model.According to the computer simulation the number of cells engrafting must vary considerably to explain the different weights of the primary tumor at the end of the experiment. Once a primary tumor is established, the fractal dimension of its vasculature correlates with the tumor size. Furthermore, the fractal dimension of the tumor vasculature changes during treatment, indicating that the therapy affects the blood vessels' geometry. We corroborated these findings with a quantitative histological analysis showing that the blood vessel density is depleted during radiotherapy and cisplatin chemotherapy. The CaTSiT computer model reveals that chemotherapy influences the tumor's therapeutic susceptibility and its metastatic spreading behavior.Using a system biological approach in combination with xenograft models and computer simulations revealed that the usage of chemotherapy and radiation therapy determines the spreading behavior by changing the blood vessel geometry of the primary tumor.

SUBMITTER: Frenzel T

PROVIDER: S-EPMC5673169 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model.

Frenzel Thorsten T Hoffmann Bertin B Schmitz Rüdiger R Bethge Anja A Schumacher Udo U Wedemann Gero G

PloS one 20171106 11

<h4>Background</h4>Tumor vasculature is critical for tumor growth, formation of distant metastases and efficiency of radio- and chemotherapy treatments. However, how the vasculature itself is affected during cancer treatment regarding to the metastatic behavior has not been thoroughly investigated. Therefore, the aim of this study was to analyze the influence of hypofractionated radiotherapy and cisplatin chemotherapy on vessel tree geometry and metastasis formation in a small cell lung cancer x ...[more]

PMID: 29107953

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Project description:Radiotherapy and surgery are curative treatment options for localized prostate cancer (PCa) with a 5-year survival rate of nearly 100%. Once PCa cells spread into distant organs, such as bone, the overall survival rate of patients drops dramatically. The metastatic cascade and organotropism of PCa cells are regulated by different cellular subtypes, organ microenvironment, and their interactions. This cross-talk leads to pre-metastatic niche formation that releases chemo-attractive factors enforcing the formation of distant metastasis. Biological characteristics of PCa metastasis impacting on metastatic sites, burden, and latency is of clinical relevance. Therefore, the implementation of modern hybrid imaging technologies into clinical routine increased the sensitivity to detect metastases at earlier stages. This enlarged the number of PCa patients diagnosed with a limited number of metastases, summarized as oligometastatic disease. These patients can be treated with androgen deprivation in combination with local-ablative radiotherapy or radiopharmaceuticals directed to metastatic sites. Unfortunately, the number of patients with disease recurrence is high due to the enormous heterogeneity within the oligometastatic patient population and the lack of available biomarkers with predictive potential for metastasis-directed radiotherapy. Another, so far unmet clinical need is the diagnosis of minimal residual disease before onset of clinical manifestation and/or early relapse after initial therapy. Here, monitoring of circulating and disseminating tumor cells in PCa patients during the course of radiotherapy may give us novel insight into how metastatic spread is influenced by radiotherapy and vice versa. In summary, this review critically compares current clinical concepts for metastatic PCa patients and discuss the implementation of recent preclinical findings improving our understanding of metastatic dissemination and radiotherapy resistance into standard of care.

Project description:BackgroundNHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapy.MethodsTumor-bearing C57Bl/6 mice were treated with NHS-IL2 alone (5 mg/kg; days 7-9), fractionated radiotherapy (3.6 Gy; days 0-4) plus cisplatin (4 mg/kg; day 0), or the triple combination. Metastatic NSCLC patients who achieved disease control with first-line palliative chemotherapy were enrolled in the phase Ib trial. Patients received local irradiation (5x 4 Gy) of a single pulmonary nodule. Dose-escalated NHS-IL2 was administered as 1-h intravenous infusion on 3 consecutive days every 3 weeks.ResultsNHS-IL2 plus radiotherapy induced immune response activation and complete tumor growth regressions in 80%-100% of mice. In patients with metastatic NSCLC treated with NHS-IL2 (3, 3, and 7 patients in the 0.15-mg/kg, 0.30-mg/kg, and 0.45-mg/kg cohorts, respectively), maximum tolerated dose was not reached. Most frequently reported adverse events were fatigue, anorexia, and rash. Transient increases in leukocyte subsets were observed. In 3 patients, thyroid gland dysfunction occurred. No objective responses were reported; long-term survival was observed in 2 patients, including 1 patient with long-term tumor control.ConclusionsCombining NHS-IL2 with radiotherapy achieved synergistic antitumor activity in preclinical studies, supporting the use in lung cancer patients. This combination was well tolerated and 2 of 13 patients achieved long-term survival.Trial registrationClinicalTrials.gov NCT00879866.

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Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model.

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Radiotherapy and chemotherapy change vessel tree geometry and metastatic spread in a small cell lung cancer xenograft mouse tumor model.

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