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1.
Adv Exp Med Biol ; 1232: 131-143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893404

RESUMO

Hypoxia, one of the hallmarks of cancer, is caused by an insufficient oxygen supply, mostly due to a chaotic, deficient tumor microcirculation. Apart from a hypoxia-mediated resistance to standard therapies, modulated gene and protein expression, genetic instability and malignant progression, hypoxia also plays a pivotal role in anti-cancer immune responses by (a) reducing survival, cytolytic and migratory activity of effector cells such as CD4+ cells, CD8+ cytotoxic T cells, natural killer-like T cells and natural killer cells, (b) reducing the production and release of effector cytokines, (c) supporting immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and M2 macrophages, (d) increasing the production and release of immunosuppressive cytokines, and (e) inducing the expression of immune checkpoint inhibitors. In this minireview, immunosuppressive effects of hypoxia- and HIF-1a-driven traits in cancers are described.


Assuntos
Hipóxia , Células Supressoras Mieloides , Neoplasias , Humanos , Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Microambiente Tumoral/imunologia
2.
Adv Exp Med Biol ; 1232: 169-176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893407

RESUMO

Inhospitable conditions within the tumor microenvironment (TME) are a characteristic feature ('hallmark') of most solid malignancies. Regional tumor hypoxia is a primary deficiency since it plays a key role in malignant progression. Severe hypoxia is often associated with other detrimental conditions in the TME as a consequence of hypoxia-/HIF-1α-induced (with/without oncogene-direction and/or reciprocal interaction of cancer cells with TME cells) metabolic re-programming, exorbitant extracellular adenosine (ADO) generation and VEGF overexpression/VEGF-R activation. Re-programming of the tumor metabolism inter alia includes a 'selfish' upregulation of aerobic glycolysis/glycolytic flux ('Warburg effect'), a strongly enhanced glutaminolysis in tumor cells, ketogenesis in cancer-associated fibroblasts, and an acceleration of the tryptophan uptake/intensified catabolism yielding kynurenine, which can support the malignant phenotype. Aerobic glycolysis and glutaminolysis result in lactate accumulation (up to 40 mM), and together with the enhanced ketogenesis and CO2/carbonic acid production lead to extracellular acidosis (pHe < 6.8). These traits of the TME individually or collectively operate towards cancer progression via e.g. promotion of genetic instability and mutation, resistance to apoptosis, clonal selection, limitless cell survival and sustained proliferation, continuous angiogenesis and tumor growth, local invasion and distant metastasis, anti-tumor immunosuppression and resistance to therapy.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias , Hipóxia Tumoral , Microambiente Tumoral , Linhagem Celular Tumoral , Progressão da Doença , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/fisiopatologia , Fenótipo
3.
Expert Opin Biol Ther ; 20(1): 23-33, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31714156

RESUMO

Introduction: Lung cancer is a devastating disease with poor overall survival. Despite significant advances in the treatment of lung cancers using radiochemotherapy, targeted therapies and/or immune therapies prognosis remains poor. The capacity of natural killer (NK) cells to provide a first line of defense that can bridge and orchestrate innate and 'downstream' adaptive immune responses renders them to be an ideal platform on which to base new cancer therapeutics.Areas covered: We provide an overview of the mechanisms controlling the effector functions of NK cells, tumor-directed immune escape, the impact and influence of NK cells on the development of effective, protective anti-tumor immunity and the therapeutic potential of combined cytokine-, complement-dependent- and antibody-dependent cellular cytotoxicity (CDC/ADCC), NK-92-, KIR mismatch- and CAR-NK cell-based therapies.Expert opinion: Despite promising results of immuno-oncological approaches, a relevant proportion of patients do not profit from these therapies, partly due to an ineffective NK cell activation, a lack of tumor-specific NK cells, an upregulated expression of checkpoint pathways, and a low mutational burden, which hinders the development of long-term adaptive immunity. Strategies that re-activate NK cells in combination with other therapies are therefore likely to be beneficial for the clinical outcome of patients with lung cancer.Abbreviations: ADCC: antibody-dependent cell-mediated cytotoxicity; ALK: anaplastic lymphoma kinase; CAR: chimeric antigen receptor; CDC: complement-dependent cytotoxicity; CEACAM-1: carcinoembryonic antigen-related cell adhesion molecule 1; DC: dendritic cell; DNAM: activating, maturation receptor; EGFR, epidermal growth factor receptor; EMT: epithelial-to-mesenchymal transition; EpCAM: epithelial cell adhesion molecule; GM-CSF: granulocyte monocyte colony stimulating factor; HIF: hypoxia inducible factor; IDO, indoleamine 2,3-dioxygenase; IFN: interferon; IL: interleukin; ITIM/ITAM: immune tyrosine-based inhibitory/activatory motif; KIR: killer cell immunoglobulin-like receptor; LAG-3: lymphocyte activation gene 3; MDSC: myeloid derived suppressor cells; MICA/B: MHC class I-related proteins A/B; MHC: major histocompatibility complex; mTOR: mechanistic target of rapamycin; NCAM: neuronal adhesion molecule; NCR: natural cytotoxicity receptor; NK: natural killer; NSCLC: non-small cell lung cancer; PD-1: programmed cell death 1; PS: phosphatidylserine; SCLC: small cell lung cancer; STAT: signal transducer and activator of transcription; TAM: tumor-associated M2 macrophages; TCR: T cell receptor; TIGIT: T cell immunoglobulin and ITIM domain; Tim-3: T cell immunoglobulin- and mucin domain-containing 3; TNF: tumor necrosis factor; ULBP: UL16-binding protein.

4.
Int J Hyperthermia ; 36(1): 938-952, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31535588

RESUMO

Purpose: The temporal and spatial formation of the temperature field and its changes during/upon water-filtered infrared-A (wIRA)-irradiation in porcine skin and subcutis were investigated in vivo in order to get a detailed physical basis for thermotherapy of superficial tumors and infections caused by thermosensitive microbial pathogens (e.g., Mycobacterium ulcerans causing Buruli ulcer). Methods: Local wIRA-hyperthermia was performed in 11 anesthetized piglets using 85.0 mW cm-2, 103.2 mW cm-2 and 126.5 mW cm-2, respectively. Invasive temperature measurements were carried out simultaneously in 1-min intervals using eight fiber-optical probes at different tissue depths between 2 and 20 mm, and by an IR thermometer at the skin surface. Results: Tissue temperature distribution depended on incident irradiance, exposure time, tissue depths and individual 'physiologies' of the animals. Temperature maxima were found at depths between 4 and 7 mm, exceeding skin surface temperatures by about 1-2 K. Tissue temperatures above 37 °C, necessary to eradicate M. ulcerans at depths <20 mm, were reached reliably. Conclusions: wIRA-hyperthermia may be considered as a novel therapeutic option for treatment of local skin infections caused by thermosensitive pathogens (e.g., in Buruli ulcer). To ensure temperatures required for heat treatment of superficial tumors deeper than 4 mm, the incident irradiance needed can be controlled either by (a) invasive temperature measurements or (b) control of skin surface temperature and considering possible temperature increases up to 1-2 K in underlying tissue.

5.
Int J Radiat Biol ; 95(7): 912-919, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30822194

RESUMO

In the early 1920s, Warburg published experimental data on the enhanced conversion of glucose to pyruvate (followed by lactate formation) even in the presence of abundant oxygen (aerobic glycolysis, Warburg effect). He attributed this metabolic trait to a respiratory injury and considered this a universal metabolic alteration in carcinogenesis. This interpretation of the data was questioned since the early 1950s. Realistic causative mechanisms and consequences of the Warburg effect were described only during the past 15 years and are summarized in this article. There is clear evidence that mitochondria are not defective in most cancers. Aerobic glycolysis, a key metabolic feature of the Warburg phenotype, is caused by active metabolic reprogramming required to support sustained cancer cell proliferation and malignant progression. This metabolic switch is directed by altered growth factor signaling, hypoxic or normoxic activation of HIF-1α- transcription, oncogene activation or loss-of-function of suppressor genes, and is implemented in the hostile tumor microenvironment. The 'selfish' reprogramming includes (a) overexpression of glucose transporters and of key glycolytic enzymes, and an accelerated glycolytic flux with subsequent accumulation and diversion of glycolytic intermediates for cancer biomass synthesis, (b) high-speed ATP production that meets the energy demand, and (c) accumulation of lactate which drives tumor progression and largely contributes to tumor acidosis, which in turn synergistically favors tumor progression and resistance to certain antitumor therapies, and compromises antitumor immunity. Altogether, the Warburg effect is the central contributor to the cancer progression machinery.


Assuntos
Reprogramação Celular , Neoplasias/metabolismo , Neoplasias/patologia , Oxigênio/metabolismo , Trifosfato de Adenosina/química , Animais , Biomassa , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Genes Supressores de Tumor , Glucose/metabolismo , Glicólise , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Ácido Láctico/metabolismo , Mitocôndrias/metabolismo , Oncogenes , Transdução de Sinais , Transcrição Genética , Microambiente Tumoral
6.
Strahlenther Onkol ; 195(4): 352-361, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30747241

RESUMO

BACKGROUND: Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient. PATIENT: Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy. RESULTS: Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. CONCLUSION: A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.


Assuntos
Transferência Adotiva , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/métodos , Células Matadoras Naturais/transplante , Neoplasias Pulmonares/terapia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Proteínas de Choque Térmico HSP70/sangue , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Planejamento da Radioterapia Assistida por Computador , Tomografia Computadorizada por Raios X
7.
Adv Exp Med Biol ; 1072: 171-175, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30178341

RESUMO

The metabolic tumor microenvironment (TME) is characterized inter alia by critical oxygen depletion (hypoxia/anoxia), extracellular acidosis (pH ≤ 6.8), high lactate levels (up to 40 mM in heterogeneously distributed areas), strongly elevated adenosine concentrations (10-100 µM) and declining nutrient resources. These TME features are major drivers, e.g., for genetic instability, intratumor heterogeneity, malignant progression and development of resistance to conventional anticancer therapies. In this context, hypoxia-dependent (and non-hypoxic) HIF-1α activation plays a key role in orchestrating a multifaceted (local) suppression of innate and adaptive antitumor immune responses (and of immune-based tumor treatment). Besides the characteristic traits mentioned, the immune-suppressive actions can additionally be triggered by an (over-)expression of VEGF and activation of VEGFR, and externalisation of phosphatidylserine from the inner to the outer membrane leaflet of cells and exosomes. Altogether, and even individually, these features provide strong immune-suppressive signals. The downstream effects of an enhanced HIF-1α expression include (a) an activation of immune-suppressive effects (recruitment and stimulation of immune-suppressor cells [e.g., Treg, MDSC], secretion of immune-suppressive TH2-type cytokines), and (b) inhibition of antitumor immune responses (inhibition of immune cell actions [e.g., NK, NKT, CD4+, CD8+], inhibition of antigen-presenting cells [e.g., DC], reduced production of immune-stimulatory TH1-type cytokines).


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias/patologia , Evasão Tumoral/fisiologia , Hipóxia Tumoral/fisiologia , Microambiente Tumoral/fisiologia , Animais , Progressão da Doença , Humanos , Neoplasias/metabolismo
8.
Adv Exp Med Biol ; 1072: 189-194, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30178344

RESUMO

Tumor hypoxia is a major factor inducing resistance to radiotherapy. Spatial limitation in oxygen (O2) diffusion usually leads to chronic hypoxia, whereas temporary shut-down of perfusion or fluctuations in red blood cell flux can cause acute hypoxia. Since the role of temporal heterogeneity of pO2 in acute hypoxia during radiotherapy remains unclear, this study focuses on analyzing the influence of temporal heterogeneity of tumor hypoxia upon radiotherapy by modeling the temporal variance of acute hypoxia. The computational simulation was conducted on digital 2D tumor phantoms. The O2 diffusion and consumption within the tumor tissues were calculated using the reaction-diffusion equation. A total of nine experimental tumor lines (FaDu, GL, C3H, RIF, SCCVII, KHT, MEF, MTG, HT29) were modeled according to known pO2 distributions. Each tumor line was first simulated 36 times with various temporal heterogeneities (dynamic hypoxia) and once again without temporal heterogeneity (static hypoxia). Temporal pO2 fluctuations were modeled according to known red blood cell (RBC) fluxes. All tumor phantoms were irradiated with 30 fractions of 2 Gy. Cell survival was calculated as a function of pO2 and radiation dose via linear quadratic model. The simulation results indicate that the temporal heterogeneity varies with different tumor types, and tumor line HT29 shows the most significant impact of temporal heterogeneity upon the treatment effect. The ratio between the surviving fractions without and with temporal variance ranges from 1.44 to 6.28. Given the same mean pO2, the fraction of killed tumor cells in dynamic hypoxia is higher than in static hypoxia. A temporal heterogeneity index (THI) denoting normalized average pO2 temporal variance is proposed. The results show that for similar mean tumor pO2, a strong inverse correlation between THI and the surviving fraction is observed for each tumor line. THI is highly proportional to the fraction of acute hypoxia and to the RBC flux. The proposed THI corresponds well to the fraction of acute hypoxia.


Assuntos
Neoplasias Experimentais/patologia , Tolerância a Radiação/fisiologia , Hipóxia Tumoral/fisiologia , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Neoplasias Experimentais/radioterapia
9.
Int J Hyperthermia ; 35(1): 26-36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29745269

RESUMO

Thermography-controlled, water-filtered infrared-A (wIRA) is a novel, effective and approved heating technique listed in the ESHO quality assurance guidelines for superficial hyperthermia clinical trials (2017). In order to assess the special features and the potential of wIRA-hyperthermia (wIRA-HT), detailed and updated information about its physical and photobiological background is presented. wIRA allows for (a) application of high irradiances without skin pain and acute grade 2-4 skin toxicities, (b) prolonged, therapeutically relevant exposure times using high irradiances (150-200 mW/cm2) and (c) faster and deeper heat extension within tissues. The deeper radiative penetration depth is mainly caused by forward Mie-scattering. At skin surface temperatures of 42-43 °C, the effective heating depth is 15 mm (T ≥ 40 °C) and 20 mm (T ≥ 39.5 °C). Advantages of wIRA include its contact-free energy input, easy power steering by a feed-back loop, extendable treatment fields, real-time and noninvasive surface temperature monitoring with observation of dynamic changes during HT, and - if necessary - rapid protection of temperature-sensitive structures. wIRA makes the compliant heating of ulcerated and/or bleeding tumors possible, allows for HT of irregularly shaped and diffusely spreading tumors, is independent of individual body contours, allows for very short 'transits' between HT and RT (1-4 min) or continuous heating between both therapeutic interventions. New treatment options for wIRA-HT may include malignant melanoma, vulvar carcinoma, skin metastases of different primary tumors, cutaneous T-and B-cell lymphoma, large-area hemangiomatosis, inoperable squamous cell, basal cell and eccrine carcinoma of the skin with depth extensions ≤20 mm.


Assuntos
Hipertermia Induzida/métodos , Raios Infravermelhos/uso terapêutico , Neoplasias/terapia , Água/química , Humanos , Neoplasias/patologia
10.
Front Oncol ; 7: 226, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29018770

RESUMO

Radiation biology is a highly interdisciplinary field at the interface of biology, physics, and medicine. It is characterized by rapid advances in biological and technical knowledge. The potential for using these advances to optimize medical care, radiation protection, and related fields can be exploited only with complementary activities to support the education of young academics. A small number of academic institutions have committed resources into radiation-related courses and curricula; however, few offer a comprehensive interdepartmental research and training program. At the Technical University of Munich (TUM), a full Master of Science (MSc) course in radiation biology has been established. This article describes the TUM MSc radiation biology program, discusses the scope of the field, the teaching goals, and the interdisciplinary curriculum. Detailed information on the full MSc program can be found continuously updated at www.radonc.med.tum.de/masterradiationbiology.

11.
Strahlenther Onkol ; 193(10): 791-799, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28770295

RESUMO

BACKGROUND: PET-CT is widely used for both the staging and planning of primary or neoadjuvant chemoradiotherapy for esophageal cancer. Inclusion of PET-CT information into radiotherapy planning often leads to substantial modifications of the target volume. In the case of detection of distant metastases, it may also result in a switch to a palliative treatment approach. This spares patients from therapy-related toxicities that provide no clinical benefit. However, due to a lack of studies, it is currently unclear whether the advantages of PET-CT also translate into a measurable improvement in patient survival. PATIENTS AND METHODS: A retrospective analysis assessed the survival data of 145 patients with esophageal carcinoma stages I (eight patients; 5%), II (45; 31%), III (79; 55%), IV (8; 5%) and unknown (5; 4%). Patients were treated between 1999 and 2014 either with primary chemoradiation (n = 101) or neoadjuvant chemoradiation at the Department of Radiation Oncology, University Medical Center Mainz, followed by transabdominal or transthoracic tumor resection (n = 44). Of the 145 patients, 64 (44%) had undergone PET-CT. RESULTS: Univariate analysis showed the use of PET-CT to be associated with significantly longer local recurrence-free survival (p = 0.006) and tended to translate into a measurable improvement of overall survival (p = 0.071). Since more patients underwent surgery in the group planned using PET-CT (20% vs. 44%; p = 0.002), we carried out a multivariate Cox regression analysis to adjust for this possible confounding factor. Surgery (p = 0.042; HR 0.55; 95% confidence interval: 0.31-0.98) as well as the use of PET-CT (p = 0.048; HR 0.60; 95% confidence interval: 0.36-0.99) nearly halved the risk of local recurrence. It was only in the group of patients with PET-CT that a trend towards a shorter overall survival was evident in lymph node-positive patients (p = 0.16), whereas nodal stage did not impact on survival in patients staged without PET-CT (p = 0.97). CONCLUSION: To the best of our knowledge these data suggest for the first time that the use of PET-CT in the framework of staging and planning of primary or neoadjuvant chemoradiotherapy for esophageal cancer has a favorable impact on patient survival.


Assuntos
Quimiorradioterapia/mortalidade , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/radioterapia , Recidiva Local de Neoplasia/mortalidade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Planejamento da Radioterapia Assistida por Computador/estatística & dados numéricos , Radioterapia Guiada por Imagem/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/estatística & dados numéricos , Neoplasias Esofágicas/diagnóstico por imagem , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Prevalência , Prognóstico , Dosagem Radioterapêutica , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento
12.
Adv Exp Med Biol ; 977: 91-99, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28685432

RESUMO

In this chapter we allude to a series of facts and fallacies often encountered in the description of tumor hypoxia, a relevant trait of the tumor microenvironment and a paramount driver of tumor aggressiveness and treatment resistance. The critical role of diffusion distances, terminological inconsistencies considering O2 partial pressures vs. O2 concentrations and with it the use of inept units, the impact of O2 depletion on proliferation and cell viability, the switch in the Warburg dogma , the distribution of hypoxic subvolumes within a tumor, the involvement of O2 diffusion shunts in the development of chronic hypoxia, and the role of endogenous biomarkers as surrogates for the assessment of hypoxia are discussed in more detail. Special emphasis is put on the clinical relevance of these misconceptions and misinterpretations and their impact on the assessment of hypoxia as well as hypoxia-targeted treatment planning.


Assuntos
Neoplasias/metabolismo , Consumo de Oxigênio/fisiologia , Oxigênio/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Difusão , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Hipóxia Tumoral/fisiologia , Microambiente Tumoral
13.
Adv Exp Med Biol ; 977: 101-107, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28685433

RESUMO

We have established a novel in situ protein analysis pipeline, which is built upon highly sensitive, multichannel immunofluorescent staining of paraffin sections of human and xenografted tumor tissue. Specimens are digitized using slide scanners equipped with suitable light sources and fluorescence filter combinations. Resulting digital images are subsequently subjected to quantitative image analysis using a primarily object-based approach, which comprises segmentation of single cells or higher-order structures (e.g., blood vessels), cell shape approximation, measurement of signal intensities in individual fluorescent channels and correlation of these data with positional information for each object. Our approach could be particularly useful for the study of the hypoxic tumor microenvironment as it can be utilized to systematically explore the influence of spatial factors on cell phenotypes, e.g., the distance of a given cell type from the nearest blood vessel on the cellular expression of hypoxia-associated biomarkers and other proteins reflecting their specific state of activation or function. In this report, we outline the basic methodology and provide an outlook on possible use cases.


Assuntos
Biomarcadores Tumorais/análise , Hipóxia Tumoral/genética , Microambiente Tumoral/fisiologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Heterogeneidade Genética , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica/métodos , Microtomia/métodos , Microambiente Tumoral/genética
14.
Adv Exp Med Biol ; 977: 109-117, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28685434

RESUMO

Malignant growth usually leads to the depletion of oxygen (O2) supply in most solid tumors. Hypoxia can cause resistance to standard radiotherapy, some chemotherapy and immunotherapy. Furthermore, it can also trigger malignant progression by modulating gene expression and inducing genetic instability. The relationship between microvasculature, perfusion and tumor hypoxia has been intensively studied and many computational simulations have been developed to model tissue O2 transport. Usually simplified 2D phantoms are used to investigate tumor hypoxia and it is assumed that vessels are perpendicular to the region of interest and randomly distributed across the domain. Such idealistic topology overlooks vascular heterogeneity and is not accurate enough to approximate real scenarios. In addition, experimental verification of the spatial gradient of computational simulations is not directly feasible. Realistic vasculature obtained from fluorescence imaging imported as geometry for partial differential equations solving did not receive necessary attention so far. Therefore, we established a computational simulation of in vivo conditions using experimental data obtained from dorsal skin window chamber tumor preparations in nude rats for the verification of computational results. Tumor microvasculature was assessed by fluorescence microscopy. Since the conventional finite difference method can hardly satisfy the real measurements, we established a finite element method (FEM) for the experimental data in this study. Realistic 2D tumor microvasculature was reconstructed by segmenting fluorescence images and then translated into FEM topology. O2 distributions and the O2 gradients were obtained by solving reaction-diffusion equations. The simulation results show that the development of tumor hypoxia is greatly influenced by the irregular architecture and function of microvascular networks.


Assuntos
Simulação por Computador , Cultura em Câmaras de Difusão , Microvasos/metabolismo , Pele/irrigação sanguínea , Pele/metabolismo , Hipóxia Tumoral/fisiologia , Animais , Difusão , Células HT29 , Xenoenxertos , Humanos , Microvasos/patologia , Transplante de Neoplasias/instrumentação , Transplante de Neoplasias/métodos , Oxigênio/metabolismo , Ratos , Ratos Nus , Pele/patologia
15.
Front Oncol ; 7: 132, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28713771

RESUMO

Hyperthermia (HT) is one of the hot topics that have been discussed over decades. However, it never made its way into primetime. The basic biological rationale of heat to enhance the effect of radiation, chemotherapeutic agents, and immunotherapy is evident. Preclinical work has confirmed this effect. HT may trigger changes in perfusion and oxygenation as well as inhibition of DNA repair mechanisms. Moreover, there is evidence for immune stimulation and the induction of systemic immune responses. Despite the increasing number of solid clinical studies, only few centers have included this adjuvant treatment into their repertoire. Over the years, abundant prospective and randomized clinical data have emerged demonstrating a clear benefit of combined HT and radiotherapy for multiple entities such as superficial breast cancer recurrences, cervix carcinoma, or cancers of the head and neck. Regarding less investigated indications, the existing data are promising and more clinical trials are currently recruiting patients. How do we proceed from here? Preclinical evidence is present. Multiple indications benefit from additional HT in the clinical setting. This article summarizes the present evidence and develops ideas for future research.

16.
Physiol Meas ; 38(2): 188-204, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28055983

RESUMO

Positron-emission tomography (PET) with hypoxia specific tracers provides a noninvasive method to assess the tumor oxygenation status. Reaction-diffusion models have advantages in revealing the quantitative relation between in vivo imaging and the tumor microenvironment. However, there is no quantitative comparison of the simulation results with the real PET measurements yet. The lack of experimental support hampers further applications of computational simulation models. This study aims to compare the simulation results with a preclinical [18F]FMISO PET study and to optimize the reaction-diffusion model accordingly. Nude mice with xenografted human squamous cell carcinomas (CAL33) were investigated with a 2 h dynamic [18F]FMISO PET followed by immunofluorescence staining using the hypoxia marker pimonidazole and the endothelium marker CD 31. A large data pool of tumor time-activity curves (TAC) was simulated for each mouse by feeding the arterial input function (AIF) extracted from experiments into the model with different configurations of the tumor microenvironment. A measured TAC was considered to match a simulated TAC when the difference metric was below a certain, noise-dependent threshold. As an extension to the well-established Kelly model, a flow-limited oxygen-dependent (FLOD) model was developed to improve the matching between measurements and simulations. The matching rate between the simulated TACs of the Kelly model and the mouse PET data ranged from 0 to 28.1% (on average 9.8%). By modifying the Kelly model to an FLOD model, the matching rate between the simulation and the PET measurements could be improved to 41.2-84.8% (on average 64.4%). Using a simulation data pool and a matching strategy, we were able to compare the simulated temporal course of dynamic PET with in vivo measurements. By modifying the Kelly model to a FLOD model, the computational simulation was able to approach the dynamic [18F]FMISO measurements in the investigated tumors.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Misonidazol/análogos & derivados , Modelos Biológicos , Neoplasias de Células Escamosas/metabolismo , Oxigênio/metabolismo , Tomografia por Emissão de Pósitrons , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Difusão , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Interpretação de Imagem Assistida por Computador , Camundongos , Camundongos Nus , Neoplasias de Células Escamosas/diagnóstico por imagem , Neoplasias de Células Escamosas/patologia , Hipóxia Tumoral , Microambiente Tumoral
17.
Proc Natl Acad Sci U S A ; 114(6): E990-E998, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28115701

RESUMO

Oncogenic human papillomaviruses (HPVs) are closely linked to major human malignancies, including cervical and head and neck cancers. It is widely assumed that HPV-positive cancer cells are under selection pressure to continuously express the viral E6/E7 oncogenes, that their intracellular p53 levels are reconstituted on E6/E7 repression, and that E6/E7 inhibition phenotypically results in cellular senescence. Here we show that hypoxic conditions, as are often found in subregions of cervical and head and neck cancers, enable HPV-positive cancer cells to escape from these regulatory principles: E6/E7 is efficiently repressed, yet, p53 levels do not increase. Moreover, E6/E7 repression under hypoxia does not result in cellular senescence, owing to hypoxia-associated impaired mechanistic target of rapamycin (mTOR) signaling via the inhibitory REDD1/TSC2 axis. Instead, a reversible growth arrest is induced that can be overcome by reoxygenation. Impairment of mTOR signaling also interfered with the senescence response of hypoxic HPV-positive cancer cells toward prosenescent chemotherapy in vitro. Collectively, these findings indicate that hypoxic HPV-positive cancer cells can induce a reversible state of dormancy, with decreased viral antigen synthesis and increased therapeutic resistance, and may serve as reservoirs for tumor recurrence on reoxygenation.


Assuntos
Senescência Celular/genética , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Papillomaviridae/genética , Hipóxia Celular , Linhagem Celular , Linhagem Celular Tumoral , Feminino , Células HCT116 , Células HeLa , Células Hep G2 , Interações Hospedeiro-Patógeno/genética , Humanos , Hipóxia , Células MCF-7 , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/virologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/metabolismo , Papillomaviridae/fisiologia , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
18.
Int J Hyperthermia ; 33(2): 227-236, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27618745

RESUMO

PURPOSE: Evaluation of the efficacy and toxicity of a new setup of thermographically controlled water-filtered infra-red-A (wIRA) superficial hyperthermia (HT) combined with hypofractionated re-irradiation (re-RT) to treat large-sized breast cancer recurrences. METHODS: Records of 73 heavily pre-irradiated patients with 103 treatment regions, treated from September 2009 to July 2015 were retrospectively analysed. Sixty-four patients with macroscopic disease were treated with 94 regions including 46 patients with lymphangiosis carcinomatosa. Hypofractionated RT consisted of 4 Gy once per week up to a total dose of 20 Gy delivered within 1-4 min after wIRA-HT. Heating of tumour nodules and diffusely spreading cancer lesions was performed under real-time thermographic temperature monitoring, maintaining the maximum skin temperature in the ROI between 42 °C and 43 °C, achieving intratumoural temperatures up to a depth of 2 cm between 39.5 °C and 42 °C. Seventeen patients received re-re-irradiation (re-re-RT) using the same HT/RT-treatment schedule. RESULTS: Response rates in patients with macroscopic disease: 61% CR, 33% PR, 5% NC and 1% PD. Local control throughout life time after CR of macroscopic disease: 59%. All nine patients with microscopic disease had CR and local control throughout lifetime. Only grade 1 toxicities were observed. CONCLUSIONS: Application of thermographically controlled wIRA-HT combined with extremely low-dose re-irradiation provides good local control throughout lifetime of heavily pre-treated breast cancer recurrences. The twin wIRA radiator provides a sufficiently homogeneous heat deposition for the treatment of larger areas. The time lag between HT and re-RT is substantially reduced. The possibility of re-re-RT opens new therapeutic options for the future.

19.
Front Immunol ; 8: 1887, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29312351

RESUMO

In this minireview, we aim to highlight key factors of the tumor microenvironment, including adenosine, lactate, acidosis, vascular endothelial growth factor, phosphatidylserine, high extracellular K+ levels, and tumor hypoxia with respect to antitumor immune functions. Most solid tumors have an immature chaotic microvasculature that results in tumor hypoxia. Hypoxia is a key determinant of tumor aggressiveness and therapy resistance and hypoxia-related gene products can thwart antitumor immune responses.

20.
Mol Imaging Biol ; 19(1): 120-129, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27379986

RESUMO

PURPOSE: Quantitative evaluation of tumor hypoxia based on H-1-(3-[18F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([18F]FMISO) positron emission tomography (PET) can deliver important information for treatment planning in radiotherapy. However, the merits and limitations of different analysis methods in revealing the underlying physiological feature are not clear. This study aimed to assess these quantitative analysis methods with the support of immunohistological data. PROCEDURES: Sixteen nude mice bearing xenografted human squamous cell carcinomas (FaDu or CAL-33) were scanned using 2-h dynamic [18F]FMISO PET. Tumors were resected and sliced, and the hypoxia marker pimonidazole was immunostained followed by H&E staining. The pimonidazole signal was segmented using a k-means clustering algorithm, and the hypoxic fraction (HF) was calculated as the hypoxic area/viable tumor-tissue-area ratio pooled over three tissue slices from the apical, center, and basal layers. PET images were analyzed using various methods including static analysis [standard uptake value (SUV), tumor-to-blood ratio (T/B), tumor-to-muscle ratio (T/M)] and kinetic modeling (Casciari αk A , irreversible and reversible two-tissue compartment k 3, Thorwarth w A k 3, Patlak K i , Logan V d , Cho K), and correlated with HF. RESULTS: No significant correlation was found for static analysis. A significant correlation between k 3 of the irreversible two-tissue compartment model and HF was observed (r = 0.61, p = 0.01). The correlation between HF and αk A of the Casciari model could be improved through reducing local minima by testing more sets of initial values (r = 0.59, p = 0.02) or by reducing the model complexity by fixing three parameters (r = 0.63, p = 0.0008). CONCLUSIONS: With support of immunohistochemistry data, this study shows that various analysis methods for [18F]FMISO PET perform differently for assessment of tumor hypoxia. A better fitting quality does not necessarily mean a higher physiological correlation. Hypoxia PET analysis needs to consider both the mathematical stability and physiological fidelity. Based on the results of this study, preference should be given to the irreversible two-tissue compartment model as well as the Casciari model with reduced parameters.


Assuntos
Misonidazol/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Hipóxia Tumoral , Animais , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Camundongos Nus , Misonidazol/química
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