Open AccessJournal Article
Tumor Oxygenation in Hormone-Dependent Tumors During Vascular Endothelial Growth Factor Receptor-2 Blockade, Hormone Ablation, and Chemotherapy
Nils Hansen-Algenstaedt,Brian R. Stoll,Timothy P. Padera,Dennis E. J. G. J. Dolmans,Daniel J. Hicklin,Dai Fukumura,Rakesh K. Jain +6 more
Reads0
Chats0
TLDR
The increased pO2 during anti-VEGFR-2 mAb and hormone ablation therapy may explain the observed beneficial effects of combining antiangiogenic or hormone therapies with radiation treatment, and is critical for optimal scheduling of these treatment modalities.Abstract:
Tumor oxygenation is critical for tumor survival as well as for response to therapy, e.g., radiation therapy. Hormone ablation therapy in certain hormone-dependent tumors and antiangiogenic therapy lead to vessel regression and have also shown beneficial effects when combined with radiation therapy. These findings are counterintuitive because vessel regression should reduce oxygen tension (pO2) in tumors, decreasing the effectiveness of radiotherapy. Here we report on the dynamics of pO2 and oxygen consumption in a hormone-dependent tumor following hormone ablation and during treatment with an anti-VEGFR-2 monoclonal antibody (mAb) or a combination of doxorubicin and cyclophosphamide; the latter combination is not known to cause vessel regression at doses used clinically. Androgen-dependent male mouse mammary carcinoma (Shionogi) was implanted into transparent dorsal skin-fold chambers in male severe combined immunodeficient mice. Thirteen days after the tumors were implanted, mice were treated with antiangiogenic therapy (anti-VEGFR-2 mAb, 1.4 mg/30 g body weight), hormone ablation by castration, or doxorubicin (6.5 mg/kg every 7 days) and cyclophosphamide (100 mg/kg every 7 days). A non-invasive in vivo method was used to measure pO2 profiles and to calculate oxygen consumption rates (Q(O2)) in tumors. Tumors treated with anti-VEGFR-2 mAb exhibited vessel regression and became hypoxic. Initial vessel regression was followed by a "second wave" of angiogenesis and increases in both pO2 and Q(O2). Hormone ablation led to tumor regression followed by an increase in pO2 coincident with regrowth. Chemotherapy led to tumor growth arrest characterized by constant Q(O2) and elevated pO2. The increased pO2 during anti-VEGFR-2 mAb and hormone ablation therapy may explain the observed beneficial effects of combining antiangiogenic or hormone therapies with radiation treatment. Thus, understanding the microenvironmental dynamics is critical for optimal scheduling of these treatment modalities.read more
Citations
More filters
Journal ArticleDOI
Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy.
TL;DR: It is proposed that this form of therapy, judiciously applied, can normalize the tumor vasculature and improve the delivery of therapeutics.
Journal ArticleDOI
Normalization of the vasculature for treatment of cancer and other diseases
TL;DR: The pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases are reviewed.
Journal ArticleDOI
Normalizing Tumor Microenvironment to Treat Cancer: Bench to Bedside to Biomarkers
TL;DR: Current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.
Journal ArticleDOI
Cellular abnormalities of blood vessels as targets in cancer.
TL;DR: Rapid vascular regrowth reflects the ongoing drive for angiogenesis and bizarre microenvironment in tumors that promote vascular abnormalities and thereby create therapeutic targets.
Journal ArticleDOI
Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization
Dai Fukumura,Rakesh K. Jain +1 more
TL;DR: Anti-angiogenic treatments directly targeting angiogenic signaling pathways as well as indirectly modulating angiogenesis show normalization of tumor vasculature and microenvironment at least transiently in both preclinical and clinical settings.
References
More filters
Journal ArticleDOI
Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.
TL;DR: It is shown that vascular endothelial growth factor (VEGF) probably functions as a hypoxia-inducible angiogenic factor and is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci and the clustering of capillaries alongside VEGF-producing cells.
Journal ArticleDOI
The biology of vascular endothelial growth factor
TL;DR: The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult.
Journal Article
Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review
TL;DR: Current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies, are summarized for predicting the acute and/or long-term response of tumors to therapy.
Journal ArticleDOI
The Histological Structure of Some Human Lung Cancers and the Possible Implications for Radiotherapy
R H Thomlinson,L H Gray +1 more
TL;DR: The Histological Structure of Some Human Lung Cancers and the Possible Implications for Radiotherapy as mentioned in this paper, and the possible implications for radiotherapy for lung cancer diagnosis and treatment.
Journal ArticleDOI
Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation.
TL;DR: The first combined, high-resolution measurements of interstitial pH and pO2 profiles between adjacent vessels in a human tumor xenograft are reported, using fluorescence ratio imaging and phosphorescence quenching microscopy.