Editorial

3 pages, 163 KiB

Open AccessEditorial

The Role of Hypoxia and the Immune System in Tumor Radioresistance

by Paul N. Span and Jan Bussink

Cancers 2019, 11(10), 1555; https://doi.org/10.3390/cancers11101555 - 14 Oct 2019

Cited by 9 | Viewed by 2416

Radiotherapy is given to a majority of patients with cancer, and remains one of the most (cost)effective treatment options available [...] Full article

(This article belongs to the Special Issue Tumor Radioresistance)

Research

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13 pages, 1641 KiB

Open AccessArticle

Hedgehog Pathway as a Potential Intervention Target in Esophageal Cancer

by Da Wang, Peter W. Nagle, Helena H. Wang, Justin K. Smit, Hette Faber, Mirjam Baanstra, Arend Karrenbeld, Roland K. Chiu, John Th.M. Plukker and Robert P. Coppes

Cancers 2019, 11(6), 821; https://doi.org/10.3390/cancers11060821 - 13 Jun 2019

Cited by 18 | Viewed by 2901

Abstract

Esophageal cancer (EC) is an aggressive disease with a poor prognosis. Treatment resistance is a major challenge in successful anti-cancer therapy. Pathological complete response after neoadjuvant chemoradiation (nCRT) is low, thus requiring therapy optimization. The Hedgehog (HH) pathway has been implicated in therapy [...] Read more.

Esophageal cancer (EC) is an aggressive disease with a poor prognosis. Treatment resistance is a major challenge in successful anti-cancer therapy. Pathological complete response after neoadjuvant chemoradiation (nCRT) is low, thus requiring therapy optimization. The Hedgehog (HH) pathway has been implicated in therapy resistance, as well as in cancer stemness. This article focusses on the HH pathway as a putative target in the treatment of EC. Immunohistochemistry on HH members was applied to EC patient material followed by modulation of 3D-EC cell cultures, fluorescence-activated cell sorting (FACS), and gene expression analysis after HH pathway modulation. Sonic Hedgehog (SHH) and its receptor Patched1 (PTCH1) were significantly enriched in EC resection material of patients with microresidual disease (mRD) after receiving nCRT, compared to the control group. Stimulation with SHH resulted in an up-regulation of cancer stemness in EC sphere cultures, as indicated by increased sphere formation after sorting for CD44+/CD24− EC cancer stem-like cell (CSC) population. On the contrary, inhibiting this pathway with vismodegib led to a decrease in cancer stemness and both radiation and carboplatin resistance. Our results strengthen the role of the HH pathway in chemoradiotherapy resistance. These findings suggest that targeting the HH pathway could be an attractive approach to control CSCs. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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18 pages, 4058 KiB

Open AccessArticle

Fibroblast-Mediated Immunoregulation of Macrophage Function Is Maintained after Irradiation

by Rodrigo Berzaghi, Muhammad Asad Ahktar, Ashraful Islam, Brede D. Pedersen, Turid Hellevik and Inigo Martinez-Zubiaurre

Cancers 2019, 11(5), 689; https://doi.org/10.3390/cancers11050689 - 17 May 2019

Cited by 23 | Viewed by 5508

Abstract

The abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly-resected non-small cell lung cancer [...] Read more.

The abilities of cancer-associated fibroblasts (CAFs) to regulate immune responses in the context of radiotherapy remain largely unknown. This study was undertaken to determine whether ionizing radiation alters the CAF-mediated immunoregulatory effects on macrophages. CAFs were isolated from freshly-resected non-small cell lung cancer tumors, while monocyte-derived macrophages were prepared from peripheral blood of healthy donors. Experimental settings included both (CAF-macrophage) co-cultures and incubations of M0 and M1-macrophages in the presence of CAF-conditioned medium (CAF-CM). Functional assays to study macrophage polarization/activation included the expression of cell surface markers, production of nitric oxide, secretion of inflammatory cytokines and migratory capacity. We show that CAFs promote changes in M0-macrophages that harmonize with both M1-and M2-phenotypes. Additionally, CAFs inhibit pro-inflammatory features of M1-macrophages by reducing nitric oxide production, pro-inflammatory cytokines, migration, and M1-surface markers expression. Radiation delivered as single-high dose or in fractioned regimens did not modify the immunoregulatory features exerted by CAFs over macrophages in vitro. Protein expression analyses of CAF supernatants showed that irradiated and non-irradiated CAFs produce approximately the same protein levels of immunoregulators. Thus, CAF-derived soluble factors mediate measurable changes on uncommitted macrophages and down-regulate pro-inflammatory features of M1-polarized macrophages. Notably, ionizing radiation does not curtail the CAF-mediated immunosuppressive effects. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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13 pages, 1145 KiB

Open AccessArticle

Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients

by Martijn van der Heijden, Monique C. de Jong, Caroline V. M. Verhagen, Reinout H. de Roest, Sebastian Sanduleanu, Frank Hoebers, C. René Leemans, Ruud H. Brakenhoff, Conchita Vens, Marcel Verheij and Michiel W. M. van den Brekel

Cancers 2019, 11(4), 583; https://doi.org/10.3390/cancers11040583 - 25 Apr 2019

Cited by 13 | Viewed by 3293

Abstract

Hypoxic head and neck tumors respond poorly to radiotherapy and can be identified using gene expression profiles. However, it is unknown whether treatment outcome is driven by acute or chronic hypoxia. Gene expression data of 398 head and neck cancers was collected. Four [...] Read more.

Hypoxic head and neck tumors respond poorly to radiotherapy and can be identified using gene expression profiles. However, it is unknown whether treatment outcome is driven by acute or chronic hypoxia. Gene expression data of 398 head and neck cancers was collected. Four clinical hypoxia profiles were compared to in vitro acute and chronic hypoxia profiles. Chronic and acute hypoxia profiles were tested for their association to outcome using Cox proportional hazard analyses. In an initial set of 224 patients, scores of the four clinical hypoxia profiles correlated with each other and with chronic hypoxia. However, the acute hypoxia profile showed a stronger association with local recurrence after chemoradiotherapy (p = 0.02; HR = 3.1) than the four clinical (chronic hypoxia) profiles (p = 0.2; HR = 0.9). An independent set of 174 patients confirmed that acute hypoxia is a stronger prognostic factor than chronic hypoxia for overall survival, progression-free survival, local and locoregional control. Multivariable analyses accounting for known prognostic factors substantiate this finding (p = 0.045; p = 0.042; p = 0.018 and p = 0.003, respectively). In conclusion, the four clinical hypoxia profiles are related to chronic hypoxia and not acute hypoxia. The acute hypoxia profile shows a stronger association with patient outcome and should be incorporated into existing prediction models. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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15 pages, 2617 KiB

Open AccessArticle

Tribbles Homolog 3 Involved in Radiation Response of Triple Negative Breast Cancer Cells by Regulating Notch1 Activation

by Yueh-Chun Lee, Wen-Ling Wang, Wei-Chao Chang, Yu-Hao Huang, Guan-Ci Hong, Hui-Lin Wang, Ying-Hsiang Chou, Hsien-Chun Tseng, Hsueh-Te Lee, Shao-Ti Li, Hsin-Lin Chen, Chun-Chieh Wu, Huei-Fan Yang, Bing-Yen Wang and Wen-Wei Chang

Cancers 2019, 11(2), 127; https://doi.org/10.3390/cancers11020127 - 22 Jan 2019

Cited by 23 | Viewed by 4352

Abstract

Breast cancer is the most common cancer for women in Taiwan and post-lumpectomy radiotherapy is one of the therapeutic strategies for this malignancy. Although the 10-year overall survival of breast cancer patients is greatly improved by radiotherapy, the locoregional recurrence is around 10% [...] Read more.

Breast cancer is the most common cancer for women in Taiwan and post-lumpectomy radiotherapy is one of the therapeutic strategies for this malignancy. Although the 10-year overall survival of breast cancer patients is greatly improved by radiotherapy, the locoregional recurrence is around 10% and triple negative breast cancers (TNBCs) are at a high risk for relapse. The aim of this paper is to understand the mechanisms of radioresistance in breast cancers which may facilitate the development of new treatments in sensitizing breast cancer toward radiation therapy. Tribbles homolog 3 (TRIB3) is a pseudokinase protein and known to function as a protein scaffold within cells. It has been reported that higher TRIB3 expression is a poor prognostic factor in breast cancer patients with radiotherapy. In this study, we investigate the involvement of TRIB3 in the radiation response of TNBC cells. We first found that the expression of TRIB3 and the activation of Notch1, as well as Notch1 target genes, increased in two radioresistant TNBC cells. Knockdown of TRIB3 in radioresistant MDA-MB-231 TNBC cells decreased Notch1 activation, as well as the CD24-CD44⁺ cancer stem cell population, and sensitized cells toward radiation treatment. The inhibitory effects of TRIB3 knockdown in self-renewal or radioresistance could be reversed by forced expression of the Notch intracellular domain. We also observed an inhibition in cell growth and accumulated cells in the G₀/G¹ phase in radioresistant MDA-MB-231 cells after knockdown of TRIB3. With immunoprecipitation and mass spectrometry analysis, we found that, BCL2-associated transcription factor 1 (BCLAF1), BCL2 interacting protein 1 (BNIP1), or DEAD-box helicase 5 (DDX5) were the possible TRIB3 interacting proteins and immunoprecipitation data also confirmed that these proteins interacted with TRIB3 in radioresistant MDA-MB-231 cells. In conclusion, the expression of TRIB3 in radioresistant TNBC cells participated in Notch1 activation and targeted TRIB3 expression may be a strategy to sensitize TNBC cells toward radiation therapy. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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14 pages, 6031 KiB

Open AccessArticle

The Response of Prostate Cancer to Androgen Deprivation and Irradiation Due to Immune Modulation

by Chun-Te Wu, Wen-Cheng Chen and Miao-Fen Chen

Cancers 2019, 11(1), 20; https://doi.org/10.3390/cancers11010020 - 26 Dec 2018

Cited by 18 | Viewed by 3634

Abstract

This study investigated changes in the immune system and the biological consequences of androgen deprivation therapy (ADT) and radiotherapy (RT) for augmenting the treatment response in prostate cancer, particularly for castration-resistant prostate cancer (CRPC). Human and murine prostate cancer cell lines were used [...] Read more.

This study investigated changes in the immune system and the biological consequences of androgen deprivation therapy (ADT) and radiotherapy (RT) for augmenting the treatment response in prostate cancer, particularly for castration-resistant prostate cancer (CRPC). Human and murine prostate cancer cell lines were used to examine the response to ADT and RT in vitro and in vivo. Biological changes following treatment and related immune modulation in the tumor microenvironment were examined. Our results showed that CRPC cells were demonstrated to be more resistant to the RT and ADT treatments. ADT increased tumor inhibition following irradiation. The underlying changes included increased cell death, attenuated myeloid-derived suppressor cell recruitment, and an increase in the number of tumor-infiltrating T cells (TILs). Furthermore, when high-dose fractionated RT was given to the primary CRPC tumor, a smaller size of secondary non-irradiated tumor associated with increased TILs was noted in ADT-treated mice. In conclusion, treatment resistance in CRPC was associated with a more immunosuppressive microenvironment. Enhanced antitumor immunity was responsible for the augmented RT-induced tumoricidal effect induced by ADT. Immune modulation could be a promising strategy for prostate cancer, especially for metastatic CRPC. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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Review

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20 pages, 999 KiB

Open AccessEditor’s ChoiceReview

Cancer Stem Cells and Radioresistance: DNA Repair and Beyond

by Alexander Schulz, Felix Meyer, Anna Dubrovska and Kerstin Borgmann

Cancers 2019, 11(6), 862; https://doi.org/10.3390/cancers11060862 - 21 Jun 2019

Cited by 186 | Viewed by 10813

Abstract

The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after [...] Read more.

The current preclinical and clinical findings demonstrate that, in addition to the conventional clinical and pathological indicators that have a prognostic value in radiation oncology, the number of cancer stem cells (CSCs) and their inherent radioresistance are important parameters for local control after radiotherapy. In this review, we discuss the molecular mechanisms of CSC radioresistance attributable to DNA repair mechanisms and the development of CSC-targeted therapies for tumor radiosensitization. We also discuss the current challenges in preclinical and translational CSC research including the high inter- and intratumoral heterogeneity, plasticity of CSCs, and microenvironment-stimulated tumor cell reprogramming. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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16 pages, 856 KiB

Open AccessReview

The 6th R of Radiobiology: Reactivation of Anti-Tumor Immune Response

by Jihane Boustani, Mathieu Grapin, Pierre-Antoine Laurent, Lionel Apetoh and Céline Mirjolet

Cancers 2019, 11(6), 860; https://doi.org/10.3390/cancers11060860 - 20 Jun 2019

Cited by 72 | Viewed by 14559

Abstract

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to [...] Read more.

Historically, the 4Rs and then the 5Rs of radiobiology explained the effect of radiation therapy (RT) fractionation on the treatment efficacy. These 5Rs are: Repair, Redistribution, Reoxygenation, Repopulation and, more recently, intrinsic Radiosensitivity. Advances in radiobiology have demonstrated that RT is able to modify the tumor micro environment (TME) and to induce a local and systemic (abscopal effect) immune response. Conversely, RT is able to increase some immunosuppressive barriers, which can lead to tumor radioresistance. Fractionation and dose can affect the immunomodulatory properties of RT. Here, we review how fractionation, dose and timing shape the RT-induced anti-tumor immune response and the therapeutic effect of RT. We discuss how immunomodulators targeting immune checkpoint inhibitors and the cGAS/STING (cyclic GMP-AMP Synthase/Stimulator of Interferon Genes) pathway can be successfully combined with RT. We then review current trials evaluating the RT/Immunotherapy combination efficacy and suggest new innovative associations of RT with immunotherapies currently used in clinic or in development with strategic schedule administration (fractionation, dose, and timing) to reverse immune-related radioresistance. Overall, our work will present the existing evidence supporting the claim that the reactivation of the anti-tumor immune response can be regarded as the 6th R of Radiobiology. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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17 pages, 493 KiB

Open AccessReview

Extracellular Vesicles as Transmitters of Hypoxia Tolerance in Solid Cancers

by Marijke I. Zonneveld, Tom G. H. Keulers and Kasper M. A. Rouschop

Cancers 2019, 11(2), 154; https://doi.org/10.3390/cancers11020154 - 29 Jan 2019

Cited by 46 | Viewed by 6094

Abstract

Tumour hypoxia is a common feature of solid tumours that contributes to poor prognosis after treatment. This is mainly due to increased resistance of hypoxic cells to radio- and chemotherapy and the association of hypoxic cells with increased metastasis development. It is therefore [...] Read more.

Tumour hypoxia is a common feature of solid tumours that contributes to poor prognosis after treatment. This is mainly due to increased resistance of hypoxic cells to radio- and chemotherapy and the association of hypoxic cells with increased metastasis development. It is therefore not surprising that an increased hypoxic tumour fraction is associated with poor patient survival. The extent of hypoxia within a tumour is influenced by the tolerance of individual tumor cells to hypoxia, a feature that differs considerably between tumors. High numbers of hypoxic cells may, therefore, be a direct consequence of enhanced cellular capability inactivation of hypoxia tolerance mechanisms. These include HIF-1α signaling, the unfolded protein response (UPR) and autophagy to prevent hypoxia-induced cell death. Recent evidence shows hypoxia tolerance can be modulated by distant cells that have experienced episodes of hypoxia and is mediated by the systemic release of factors, such as extracellular vesicles (EV). In this review, the evidence for transfer of a hypoxia tolerance phenotype between tumour cells via EV is discussed. In particular, proteins, mRNA and microRNA enriched in EV, derived from hypoxic cells, that impact HIF-1α-, UPR-, angiogenesis- and autophagy signalling cascades are listed. Full article

(This article belongs to the Special Issue Tumor Radioresistance)

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