Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma.

Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild-type counterparts expressing all isoforms (fs120, fs164, fs188, or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs.

Influence of soluble or matrix-bound isoforms of vascular endothelial growth factor-A on tumor response to vascular-targeted strategies.

Antiangiogenic therapy based on blocking the actions of vascular endothelial growth factor-A (VEGF) can lead to "normalization" of blood vessels in both animal and human tumors. Differential expression of VEGF isoforms affects tumor vascular maturity, which could influence the normalization process and response to subsequent treatment. Fibrosarcoma cells expressing only VEGF120 or VEGF188 isoforms were implanted either subcutaneously (s.

Vascular effects dominate solid tumor response to treatment with combretastatin A-4-phosphate.

Vascular-targeted therapeutics are increasingly used in the clinic. However, less is known about the direct response of tumor cells to these agents. We have developed a combretastatin-A-4-phosphate (CA4P) resistant variant of SW1222 human colorectal carcinoma cells to examine the relative importance of vascular versus tumor cell targeting in the ultimate treatment response.

Application of intravital microscopy in studies of tumor microcirculation.

To grow and progress, solid tumors develop a vascular network through co-option and angiogenesis that is characterized by multiple structural and functional abnormalities, which negatively influence therapeutic outcome through direct and indirect mechanisms. As such, the morphology and function of tumor blood vessels, plus their response to different treatments, are a vital and active area of biological research. Intravital microscopy (IVM) has played a key role in studies of tumor angiogenesis, and ongoing developments in molecular probes, imaging techniques, and postimage analysis methods have ensured its continued and widespread use.

Interstitial fluid pressure in tumors: therapeutic barrier and biomarker of angiogenesis.

Interstitial fluid pressure is elevated in virtually all solid malignant tumors as a result of abnormalities of the vasculature and interstitium. High interstitial fluid pressure is an independent predictor of disease recurrence in cervical cancer patients treated with radiotherapy, has been implicated as an important factor that impairs the delivery of chemotherapy to tumors and may influence the regulation and distribution of cytokines and growth factors. Targeted molecular treatments that inhibit angiogenesis or alter interstitial fluid dynamics also produce early reductions in interstitial fluid pressure.

The tumor microenvironment and metastatic disease.

The microenvironment of solid tumors is a heterogeneous, complex milieu for tumor growth and survival that includes features such as acidic pH, low nutrient levels, elevated interstitial fluid pressure (IFP) and chronic and fluctuating levels of oxygenation that relate to the abnormal vascular network that exists in tumors. The metastatic potential of tumor cells is believed to be regulated by interactions between the tumor cells and their extracellular environment (extracellular matrix (ECM)). These interactions can be modified by the accumulation of genetic changes and by the transient alterations in gene expression induced by the local tumor microenvironment.

Analysis of the effects of exposure to acute hypoxia on oxidative lesions and tumour progression in a transgenic mouse breast cancer model.

Background: Tumour hypoxia is known to be a poor prognostic indicator, predictive of increased risk of metastatic disease and reduced survival. Genomic instability has been proposed as one of the potential mechanisms for hypoxic tumour progression. Both of these features are commonly found in many cancer types, but their relationship and association with tumour progression has not been examined in the same model.

Interstitial permeability and elasticity in human cervix cancer.

Malignant tumors are characterized by abnormalities of the vasculature and interstitium, which may impede the distribution of drugs and imaging agents. Here we describe a method for estimating tumor interstitial permeability and elasticity based on fitting a spatio-temporal fluid dynamic model to the time course of interstitial pressure (IFP) measurements. The model assumes that sudden insertion of the IFP measurement needle transiently perturbs the steady-state fluid balance, which recovers over time as a function of the vascular and interstitial hydraulic conductivities (L(p)S and K), the interstitial bulk modulus (E) and the extracellular, extravascular volume fraction (phi).

Interstitial fluid pressure, vascularity and metastasis in ectopic, orthotopic and spontaneous tumours.

Background: High tumour interstitial fluid pressure (IFP) has been adversely linked to poor drug uptake in patients, and to treatment response following radiotherapy in cervix cancer patients. In this study we measured IFP values in a selection of murine and xenograft models, spontaneously arising or transplanted either intramuscularly (i/m) or orthotopically and analysed their relationship to tumour vascularity and metastatic spread.

Methods: KHT-C murine fibrosarcoma, ME180 and SiHa human cervix carcinoma were grown either intramuscularly (i/m), sub-cutaneously (s/c) or orthotopically.

Imaging the Modulation of Adenoviral Kinetics and Biodistribution for Cancer Gene Therapy.

See page 841 To explore systemic utilization of Epstein-Barr virus (EBV)-specific transcriptionally targeted adenoviruses, three vectors were constructed to examine kinetics, specificity, and biodistribution: adv.oriP.luc, expressing luciferase under EBV-specific control; adv.

Imaging the modulation of adenoviral kinetics and biodistribution for cancer gene therapy.

To explore systemic utilization of Epstein-Barr virus (EBV)-specific transcriptionally targeted adenoviruses, three vectors were constructed to examine kinetics, specificity, and biodistribution: adv.oriP.luc, expressing luciferase under EBV-specific control; adv.

Effects of the vascular disrupting agent ZD6126 on interstitial fluid pressure and cell survival in tumors.

Interstitial fluid pressure (IFP) is elevated in tumors due to abnormal vasculature, lack of lymphatic drainage, and alterations in the tumor interstitium. ZD6126 is a tubulin-binding agent that selectively disrupts tumor vasculature resulting in tumor necrosis. This study examined the effect of ZD6126 on tumor IFP and the response of tumors with different IFP levels to ZD6126.

Tirapazamine administered as a neoadjuvant to radiotherapy reduces metastatic dissemination.

Purpose: The level of hypoxia in primary tumors has been linked both clinically and experimentally to the incidence of metastases. This study was designed to address the effect of selectively targeting hypoxic cells in primary tumors on subsequent presentation of metastasis.

Experimental Design: The murine KHT model was used as a reproducible temporal and spatial onset of metastases is revealed following treatment of primary ( approximately 400 mm(3)) s.

Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy.

Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration of the glycolipid ligand alpha-galactosylceramide (alpha-GalCer) or the sphingosine-truncated alpha-GalCer analog OCH leads to CD40 signaling as well as the release of soluble molecules including type 1 and gamma interferons that contribute to DC maturation. This process enhances T cell immunity to antigens presented by the DC. The adjuvant activity is further amplified if APCs are stimulated through Toll-like receptor 4, suggesting that iNKT cell signals can amplify maturation induced by microbial stimuli.