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Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts.

ABSTRACT: External beam radiation therapy is a standard form of treatment for numerous cancers. Despite this, there are no approved methods to account for patient specific radiation sensitivity. In this report, Raman spectroscopy (RS) was used to identify radiation-induced biochemical changes in human non-small cell lung cancer xenografts. Chemometric analysis revealed unique radiation-related Raman signatures that were specific to nucleic acid, lipid, protein and carbohydrate spectral features. Among these changes was a dramatic shift in the accumulation of glycogen spectral bands for doses of 5 or 15 Gy when compared to unirradiated tumours. When spatial mapping was applied in this analysis there was considerable variability as we found substantial intra- and inter-tumour heterogeneity in the distribution of glycogen and other RS spectral features. Collectively, these data provide unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrate the utility of RS for detecting distinct radiobiological responses in human tumour xenografts.

SUBMITTER: Harder SJ

PROVIDER: S-EPMC4756358 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts.

Harder Samantha J SJ Isabelle Martin M DeVorkin Lindsay L Smazynski Julian J Beckham Wayne W Brolo Alexandre G AG Lum Julian J JJ Jirasek Andrew A

Scientific reports 20160217

External beam radiation therapy is a standard form of treatment for numerous cancers. Despite this, there are no approved methods to account for patient specific radiation sensitivity. In this report, Raman spectroscopy (RS) was used to identify radiation-induced biochemical changes in human non-small cell lung cancer xenografts. Chemometric analysis revealed unique radiation-related Raman signatures that were specific to nucleic acid, lipid, protein and carbohydrate spectral features. Among the ...[more]

PMID: 26883914

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Project description:Tumour cells exhibit altered metabolic pathways that lead to radiation resistance and disease progression. Raman spectroscopy (RS) is a label-free optical modality that can monitor post-irradiation biomolecular signatures in tumour cells and tissues. Convolutional Neural Networks (CNN) perform automated feature extraction directly from data, with classification accuracy exceeding that of traditional machine learning, in cases where data is abundant and feature extraction is challenging. We are interested in developing a CNN-based predictive model to characterize clinical tumour response to radiation therapy based on their degree of radiosensitivity or radioresistance. In this work, a CNN architecture is built for identifying post-irradiation spectral changes in Raman spectra of tumour tissue. The model was trained to classify irradiated versus non-irradiated tissue using Raman spectra of breast tumour xenografts. The CNN effectively classified the tissue spectra, with accuracies exceeding 92.1% for data collected 3 days post-irradiation, and 85.0% at day 1 post-irradiation. Furthermore, the CNN was evaluated using a leave-one-out- (mouse, section or Raman map) validation approach to investigate its generalization to new test subjects. The CNN retained good predictive accuracy (average accuracies 83.7%, 91.4%, and 92.7%, respectively) when little to no information for a specific subject was given during training. Finally, the classification performance of the CNN was compared to that of a previously developed model based on group and basis restricted non-negative matrix factorization and random forest (GBR-NMF-RF) classification. We found that CNN yielded higher classification accuracy, sensitivity, and specificity in mice assessed 3 days post-irradiation, as compared with the GBR-NMF-RF approach. Overall, the CNN can detect biochemical spectral changes in tumour tissue at an early time point following irradiation, without the need for previous manual feature extraction. This study lays the foundation for developing a predictive framework for patient radiation response monitoring.

Project description:PurposePoly(ADP-ribose) polymerase (PARP) inhibitors potentiate radiation therapy in preclinical models of human non-small cell lung cancer (NSCLC) and other types of cancer. However, the mechanisms underlying radiosensitization in vivo are incompletely understood. Herein, we investigated the impact of hypoxia on radiosensitization by the PARP inhibitor olaparib in human NSCLC xenograft models.Methods and materialsNSCLC Calu-6 and Calu-3 cells were irradiated in the presence of olaparib or vehicle under normoxic (21% O2) or hypoxic (1% O2) conditions. In vitro radiosensitivity was assessed by clonogenic survival assay and γH2AX foci assay. Established Calu-6 and Calu-3 subcutaneous xenografts were treated with olaparib (50 mg/kg, daily for 3 days), radiation (10 Gy), or both. Tumors (n=3/group) were collected 24 or 72 hours after the first treatment. Immunohistochemistry was performed to assess hypoxia (carbonic anhydrase IX [CA9]), vessels (CD31), DNA double strand breaks (DSB) (γH2AX), and apoptosis (cleaved caspase 3 [CC3]). The remaining xenografts (n=6/group) were monitored for tumor growth.ResultsIn vitro, olaparib showed a greater radiation-sensitizing effect in Calu-3 and Calu-6 cells in hypoxic conditions (1% O2). In vivo, Calu-3 tumors were well-oxygenated, whereas Calu-6 tumors had extensive regions of hypoxia associated with down-regulation of the homologous recombination protein RAD51. Olaparib treatment increased unrepaired DNA DSB (P<.001) and apoptosis (P<.001) in hypoxic cells of Calu-6 tumors following radiation, whereas it had no significant effect on radiation-induced DNA damage response in nonhypoxic cells of Calu-6 tumors or in the tumor cells of well-oxygenated Calu-3 tumors. Consequently, olaparib significantly increased radiation-induced growth inhibition in Calu-6 tumors (P<.001) but not in Calu-3 tumors.ConclusionsOur data suggest that hypoxia potentiates the radiation-sensitizing effects of olaparib by contextual synthetic killing, and that tumor hypoxia may be a potential biomarker for selecting patients who may get the greatest benefit from the addition of olaparib to radiation therapy.

Project description:Radiation therapy is currently utilised in the treatment of approximately 50% of cancer patients. A move towards patient tailored radiation therapy would help to improve the treatment outcome for patients as the inter-patient and intra-patient heterogeneity of cancer leads to large differences in treatment responses. In radiation therapy, a typical treatment outcome is cell cycle arrest which leads to cell cycle synchronisation. As treatment is typically given over multiple fractions it is important to understand how variation in the cell cycle can affect treatment response. Raman spectroscopy has previously been assessed as a method for monitoring radiation response in cancer cells and has shown promise in detecting the subtle biochemical changes following radiation exposure. This study evaluated Raman spectroscopy as a potential tool for monitoring cellular response to radiation in synchronised versus unsynchronised UVW human glioma cells in vitro. Specifically, it was hypothesised that the UVW cells would demonstrate a greater radiation resistance if the cell cycle phase of the cells was synchronised to the G1/S boundary prior to radiation exposure. Here we evaluated whether Raman spectroscopy, combined with cell cycle analysis and DNA damage and repair analysis (γ-H2AX assay), could discriminate the subtle cellular changes associated with radiation response. Raman spectroscopy combined with principal component analysis (PCA) was able to show the changes in radiation response over 24 hours following radiation exposure. Spectral changes were assigned to variations in protein, specifically changes in protein signals from amides as well as changes in lipid expression. A different response was observed between cells synchronised in the cell cycle and unsynchronised cells. After 24 hours following irradiation, the unsynchronised cells showed greater spectral changes compared to the synchronised cells demonstrating that the cell cycle plays an important role in the radiation resistance or sensitivity of the UVW cells, and that radiation resistance could be induced by controlling the cell cycle. One of the main aims of cancer treatment is to stop the proliferation of cells by controlling or halting progression through the cell cycle, thereby highlighting the importance of controlling the cell cycle when studying the effects of cancer treatments such as radiation therapy. Raman spectroscopy has been shown to be a useful tool for evaluating the changes in radiation response when the cell cycle phase is controlled and therefore highlighting its potential for assessing radiation response and resistance.

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Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts.

Publications

Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts.

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