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Immunostimulation of tumor microenvironment by targeting tumor-associated macrophages with hypoxia-responsive nanocomplex for enhanced anti-tumor therapy.

Tumor-associated macrophages (TAMs), which dampen the therapeutic efficacy of cancer immunotherapy, are the key players in the immunosuppres … s could transform the physicochemical properties to enhance the delivery efficiency of poly(I:C) to tumor hypoxia, where M2-like TAMs are accumulated. Furthermore, PEG-azo-PLL/poly(I:C) could successfully reduce the population of M2-like TAMs in hypoxic tumors and promoted infiltration of CD8+ T cells in vivo, resulting in the favorable conversion of immunosupp …

MRI-Based Assessment of Brain Tumor Hypoxia: Correlation with Histology.

Cerebral hypoxia significantly impacts the progression of brain tumors and their resistance to radiotherapy. This study employed streamlined quantitative blood-oxygen-level-dependent (sqBOLD) MRI to assess the oxygen extraction fraction (OEF)-a measure of how much oxygen is being extracted from vessels, with higher OEF values indicating hypoxia. Simultaneously, we utilized vessel size imaging (VSI) to evaluate microvascular dimensions and blood volume. A cohort of ten patients, divided between those with glioma and those with brain metastases, underwent a 3 Tesla MRI scan. We generated OEF, ce

Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia.

OBJECTIVE: To examine the effect of tumor necrosis factor (TNF) blocking therapy on hypoxia in vivo, macroscopic and microscopic inflammation, and magnetic resonance imaging (MRI) results in patients with inflammatory arthritis. METHODS: Patients with inflammatory arthritis (n = 20) underwent full clinical assessment, arthroscopy, synovial biopsy, and MRI before and after initiation of biologic therapy. Macroscopic synovitis/vascularity was assessed with a visual analog scale, and tissue PO(2) (tPO(2) ) was measured at arthroscopy using a Licox probe. Cell-specific markers (CD4, CD8, CD68, CD

Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis.

Tumor hypoxia, mostly resulting from poor perfusion and anemia, is one of the key factors in inducing the development of cell clones with an aggressive and treatment-resistant phenotype that leads to rapid progression and poor prognosis. Studies in patients with solid tumors suggest that there is a range of hemoglobin (Hb) concentrations that is optimum for tumor oxygenation. When used to achieve an Hb level within this range, erythropoiesis-stimulating agents (ESAs) can be expected to increase tumor oxygenation, and this may favorably influence sensitivity to treatment as well as quality of l…

Hypoxia in tumors: pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications.

Hypoxia is a hallmark of tumors leading to (mal-)adaptive processes, development of aggressive phenotypes and treatment resistance. Based on … nts, and repair competence can be impaired or may not be affected. This detailed differentiation of tumor hypoxia may impact on our understanding of tumor biology and may aid in the development of novel treatment strategies, tumor detection by imaging and tumor targeting, and is thus of great clinical relevance.

Tumor hypoxia: a new PET imaging biomarker in clinical oncology.

Tumor hypoxia is associated with tumor progression and resistance to various treatments. Noninvasive imaging using positron emission tomography (PET) and F-18-labeled fluoromisonidazole (FMISO) was recently introduced in order to define and quantify tumor hypoxia. The FMISO uptake was closely correlated with pimonidazole immunohistochemistry and hypoxia-inducible factor 1 expression in basic studies. Tumor hypoxia in head and neck cancers and other tumors in a clinical setting may also indicate resistance to radiation and/or chemotherapy. Hypoxic imaging may thus play a new and important role …

PET and planar imaging of tumor hypoxia with labeled metronidazole.

RATIONALE AND OBJECTIVES: This study was aimed to develop 99mTc- and 68Ga-labeled metronidazole (MN) using ethylenedicysteine (EC) as a chelator and evaluate their potential use to assess tumor hypoxia. MATERIALS AND METHODS: EC-MN was labeled with 99mTc in the presence of tin (II) chloride. Labeling EC-MN with 68Ga was achieved by adding 68GaCl3 (2 mCi with 3.4 microg cold GaCl3). In vitro cellular uptakes of 99mTc- and 68Ga-EC-MN were obtained in various types of tumor cells at 0.5-4 hours. Tissue distribution and PET imaging of 99mTc and 68Ga-EC-MN were evaluated in breast tumor-bearing ra…

Hypoxia and anemia: effects on tumor biology and treatment resistance.

In locally advanced solid tumors, oxygen (O2) delivery is frequently reduced or even abolished. This is due to abnormalities of the tumor microvasculature, adverse diffusion geometries, and tumor-associated and/or therapy-induced anemia. Up to 50-60% of locally advanced solid tumors may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumor mass. In approximately 30% of pretreatment patients, a decreased O2 transport capacity of the blood as a result of tumor-associated anemia can greatly contribute to the development of tumor hypoxia. While normal tis…

Energy status parameters, hypoxia fraction and radiocurability across tumor types.

Under full nutrient in vitro conditions, the cellular adenylate energy charge of six different rodent and human tumor cell types was identical, i.e., 0.94 +/- 0.01, suggesting the potential utility of this parameter as a cell (and tissue) independent marker of nutrient deprivation and hypoxia, across tumor types. The adenylate energy charge values of tumors, arising from these cells, was reduced and variable ranging from 0.72 to 0.91 for the various tumor types. However, neither the tumor adenylate energy charge, NTP/Pi, nor PCr/Pi ratios correlated with the radiobiologic hypoxic cell fraction

Hydralazine-induced tumor hypoxia: a potential target for cancer chemotherapy.

Currently available cancer chemotherapeutic agents have been designed to exploit subtle differences in proliferation and biochemistry that are known to exist between host and malignant cells. However, chemotherapeutic agents may also be used to exploit physiological differences between cancer and normal tissue. The present study was conducted to determine whether the reduction in blood flow to the tumor (and thus oxygen delivery) induced by the vasodilator hydralazine would increase the cytotoxicity of drugs known to be more toxic in regions of reduced oxygenation. Results obtained with three

Chlorella-based bioactive oxygen generator for sustained tumor hypoxia alleviation and combined-modality tumor therapy.

The hypoxic tumor microenvironment (TME) promotes tumor progression and therapeutic resistance primarily through the activation of hypoxia-inducible factor-α (HIF-α). However, current oxygen-sensitizing strategies are hindered by low delivery efficiency, transient efficacy, and severe adverse effects. In this study, we developed a composite system (C@W) comprising Chlorella pyrenoidosa (CHL) and tungsten disulfide (WS₂). This platform synergistically integrates the photosynthetic oxygen generation capacity of CHL with the photocatalytic functionality of WS₂, enabling multimodal antitumor effic

Hypoxia-driven angiogenesis and metabolic reprogramming in vascular tumors.

Hypoxia is a hallmark of the tumor microenvironment (TME), and it plays a crucial role in the occurrence and progression in vascular tumors. Under hypoxic conditions, hypoxia-inducible factor 1-alpha (HIF-1α) is stabilized, inducing changes in the expression of various target genes involved in angiogenesis, metabolism, and cell survival. This includes the upregulation of pro-angiogenic factors like VEGF, which promotes the formation of dysfunctional blood vessels, contributing to the worsening of the hypoxic microenvironment. At the same time, hypoxia induces a metabolic shift toward glycolysi

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… Höckel et al. further discovered that tumor hypoxia (reduced pO 2 ) is associated with poor prognosis in primary cervical cancer ( Höckel et al., 1993 ; Höckel et al., 1996 ). … Aside from the factors mentioned above, several additional mechanisms also contribute to tumor hypoxia. …

Hypoxia signaling pathway: A central mediator in endocrine tumors.

Adequate oxygen levels are essential for the functioning and maintenance of biological processes in virtually every cell, albeit based on specific need. Thus, any change in oxygen pressure leads to modulated activation of the hypoxia pathway, which affects numerous physiological and pathological processes, including hematopoiesis, inflammation, and tumor development. The Hypoxia Inducible Factors (HIFs) are essential transcription factors and the driving force of the hypoxia pathway; whereas, their inhibitors, HIF prolyl hydroxylase domain (PHDs) proteins are the true oxygen sensors that criti

In Vivo Model for Testing Effect of Hypoxia on Tumor Metastasis.

Hypoxia has been implicated in the metastasis of Ewing sarcoma (ES) by clinical observations and in vitro data, yet direct evidence for its pro-metastatic effect is lacking and the exact mechanisms of its action are unclear. Here, we report an animal model that allows for direct testing of the effects of tumor hypoxia on ES dissemination and investigation into the underlying pathways involved. This approach combines two well-established experimental strategies, orthotopic xenografting of ES cells and femoral artery ligation (FAL), which induces hindlimb ischemia. Human ES cells were injected i…

Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells.

The complex and continuously evolving features of the tumor microenvironment, varying between tumor histotypes, are characterized by the presence of host cells and tumor cells embedded in a milieu shaped by hypoxia and low pH, resulting from the frequent imbalance between vascularity and tumor cell proliferation. These microenvironmental metabolic stressors play a crucial role in remodeling host cells and tumor cells, contributing to the stimulation of cancer cell heterogeneity, clonal evolution, and multidrug resistance, ultimately leading to progression and metastasis. The extracellular vesi

Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors.

Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis fo

Evaluating Tumor Hypoxia Radiosensitization Via Electron Paramagnetic Resonance Oxygen Imaging (EPROI).

PURPOSE: Tumor hypoxia contributes to aggressive phenotypes and diminished therapeutic responses to radiation therapy (RT) with hypoxic tissue being 3-fold less radiosensitive than normoxic tissue. A major challenge in implementing hypoxic radiosensitizers is the lack of a high-resolution imaging modality that directly quantifies tissue-oxygen. The electron paramagnetic resonance oxygen-imager (EPROI) was used to quantify tumor oxygenation in two murine tumor models: E0771 syngeneic transplant breast cancers and primary p53/MCA soft tissue sarcomas, with the latter autochthonous model better r…

Hypoxia-Responsive Azobenzene-Linked Hyaluronate Dot Particles for Photodynamic Tumor Therapy.

In this study, we developed ultra-small hyaluronate dot particles that selectively release phototoxic drugs into a hypoxic tumor microenviro … ynamic antitumor inhibition, suggesting its potential as an antitumor drug candidate in response to tumor hypoxia.

Occult gastric cancer presenting as hypoxia from pulmonary tumor thrombotic microangiopathy.

Pulmonary tumor thrombotic microangiopathy (PTTM) causing fatal pulmonary hypertension is a rare presentation of malignancy. In general, patients with PTTM rapidly succumb to death due to severe hypoxia. To date, very few cases of PTTM have been reported in the literature; and most of these cases were from gastric cancer and were diagnosed on post mortem autopsy, as it is extremely challenging to make an ante mortem diagnosis. We here report on a case of undiagnosed diffuse gastric cancer, presenting as worsening hypoxia. The clinical, radiographic, and echocardiographic features, and laborato

A Nanoradiosensitizer Potentiates Tumor Radiotherapy through JFK Inhibition and Hypoxia Alleviation.

Radiotherapy (RT) is a primary treatment for breast cancer, but its effectiveness is often compromised by hypoxia and intrinsic resistance mechanisms. The F-box protein JFK is overexpressed in breast cancer and is associated with reduced radiosensitivity, but specific JFK inhibitors are currently unavailable. Herein, we developed spherical nanoparticles (SNP-JC) designed to co-deliver small interfering RNA targeting JFK and catalase to the tumor, aiming to silence JFK and alleviate hypoxia to overcome RT resistance. Positron emission tomography imaging demonstrated that SNP-JC efficiently accu