Blood Vessel Maturation in Human Uveal Melanoma: Spatial Distribution of Neovessels and Mature Vasculature

Piña, Yolanda; Cebulla, Colleen M.; Murray, Timothy G.; Alegret, Armando; Dubovy, Sander R.; Boutrid, Hinda; Feuer, William J.; Mutapčić, Lejla; Jockovich, Maria Elena

doi:10.1159/000209670

Cited by 15 publications

(9 citation statements)

References 102 publications

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“…Spatial distribution of vessels (blood or lymphatic) has been investigated in some types of cancer [18–20]. Also, morphological parameters of intra-tumoral blood vessels have been linked to patient outcome in CRC and other types of cancer [21–24]. However, to our knowledge, there have been no systematic investigations on the spatial distribution of blood vessels in whole slide images (WSI) of CRC tissue except for our recent work on tumor angiogenic hotspots [4].…”

Section: Introductionmentioning

confidence: 99%

Identification of a characteristic vascular belt zone in human colorectal cancer

et al. 2017

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Blood vessels in cancerIntra-tumoral blood vessels are of supreme importance for tumor growth, metastasis and therapy. Yet, little is known about spatial distribution patterns of these vessels. Most experimental or theoretical tumor models implicitly assume that blood vessels are equally abundant in different parts of the tumor, which has far-reaching implications for chemotherapy and tumor metabolism. In contrast, based on histological observations, we hypothesized that blood vessels follow specific spatial distribution patterns in colorectal cancer tissue. We developed and applied a novel computational approach to identify spatial patterns of angiogenesis in histological whole-slide images of human colorectal cancer.A characteristic spatial pattern of blood vessels in colorectal cancerIn 33 of 34 (97%) colorectal cancer primary tumors blood vessels were significantly aggregated in a sharply limited belt-like zone at the interface of tumor tissue to the intestinal lumen. In contrast, in 11 of 11 (100%) colorectal cancer liver metastases, a similar hypervascularized zone could be found at the boundary to surrounding liver tissue. Also, in an independent validation cohort, we found this vascular belt zone: 22 of 23 (96%) samples of primary tumors and 15 of 16 (94%) samples of liver metastases exhibited the above-mentioned spatial distribution.Summary and implicationsWe report consistent spatial patterns of tumor vascularization that may have far-reaching implications for models of drug distribution, tumor metabolism and tumor growth: luminal hypervascularization in colorectal cancer primary tumors is a previously overlooked feature of cancer tissue. In colorectal cancer liver metastases, we describe a corresponding pattern at the invasive margin. These findings add another puzzle piece to the complex concept of tumor heterogeneity.

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Section: Introductionmentioning

confidence: 99%

Identification of a characteristic vascular belt zone in human colorectal cancer

et al. 2017

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“…Of note, tumors previously treated with radiation therapy displayed the highest VEGF concentrations. These results have been confirmed and have been shown to correlate with larger basal diameter and tumor height 26,27. Recently, intravitreal bevacizumab has been effectively used in multiple retinal diseases, including age-related macular degeneration, retinal vein occlusions, diabetic macular edema, and neovascularization 28–33.…”

Section: Introductionmentioning

confidence: 74%

Early SD-OCT diagnosis followed by prompt treatment of radiation maculopathy using intravitreal bevacizumab maintains functional visual acuity

Shah¹,

Houston²,

Markoe³

et al. 2012

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Purpose:To evaluate the benefits of intravitreal bevacizumab in patients with visually compromising radiation maculopathy following iodine-125 plaque brachytherapy for uveal melanoma.Methods:In this Institutional Review Board-approved, consecutive, retrospective study from 2006–2009 of patients maintaining 20/50 or better vision following treatment for visually compromising radiation maculopathy, patients were evaluated with spectral domain optical coherence tomography at 2–4 month intervals following plaque removal. Treatment with intra-vitreal bevacizumab commenced at the first signs of radiation vasculopathy on spectral domain optical coherence tomography with associated decreased best corrected visual acuity, followed by repeat injections for recurrent or persistent vasculopathic changes.Results:At 3 years following plaque brachytherapy, 81 of 159 (50.9%) patients treated for radiation maculopathy demonstrated 20/50 or better vision at median follow up of 36 months, which demonstrates significant improvement in vision as compared to the Collaborative Ocular Melanoma Study (P < 0.0001). These 81 patients were given a mean of five injections (range 1–17) over a mean of 17.6 months (range 1–54 months), starting at 15.8 months (range 3–50 months) after plaque brachytherapy. For those eyes that maintained 20/50 or better vision at the final follow-up, pretreatment mean best corrected visual acuity of 20/43 improved to 20/31.Conclusion:This study demonstrates that spectral domain optical coherence tomography can detect early vasculopathic changes secondary to radiation maculopathy and that prompt treatment with intravitreal bevacizumab may delay vision loss and maintain or possibly improve visual acuity in half of eyes diagnosed with radiation maculopathy. Radiation maculopathy remains a therapeutically manageable morbidity associated with radiation therapy for posterior uveal melanoma.

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“…Using the LH BETA T AG mouse model of retinoblastoma, we have shown that anti-angiogenic therapy primarily targets areas with high angiogenic activity, while having little to no effect in established mature blood vessels 30. We have also shown that the heterogeneity and spatial distribution of neovessels and mature vessels in ocular tumors may impact the efficacy of anti-angiogenic therapies, and may dictate the treatment modalities used 31,47. Other studies have shown that inhibition of mTOR can potentially inhibit angiogenesis by reducing VEGF-receptors (VEGFRs) 48,49.…”

Section: Discussionmentioning

confidence: 99%

Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors

Piña

Decatur

Murray

et al. 2011

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Purpose:The purpose of this study is to analyze the dose response of the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, on tumor burden and hypoxia, and study the treatment effect on vasculature in LHBETATAG retinal tumors.Methods:This study was approved by the Institutional Animal Care and Use Committee and follows Association for Research in Vision and Ophthalmology guidelines. Eighteen-week-old LHBETATAG retinal tumor eyes (n = 30) were evaluated. Mice were divided into five groups and received periocular injections once weekly for two consecutive weeks of: a) 80% DMSO (dimethyl sulfoxide, vehicle control), b) 0.00333 mg/kg, c) 0.167 mg/kg, d) 3.33 mg/kg, and e) 6.67 mg/kg of rapamycin. Tumor sections were analyzed for hypoxia, tumor burden, and vasculature with immunohistochemistry techniques.Results:Reduction in tumor burden and hypoxia was significantly different between rapamycin doses and control (P < 0.002). Eyes treated with rapamycin at 0.167, 3.33, and 6.67 mg/kg showed a significant decrease in tumor burden in comparison with the vehicle control group (P = 0.019, P = 0.001, P = 0.009, respectively) and the 0.00333 mg/kg dose response (P = 0.023, P = 0.001, P = 0.010, respectively). Eyes treated with rapamycin at 3.33 mg/kg showed a significant reduction in the amount of hypoxia in comparison with the lower concentration groups (0.00333 and 0.167 mg/kg) of rapamycin (P = 0.024 and P = 0.052, respectively). The number of mature vessels was significantly lower in the 3.33 mg/kg treated versus vehicle control (P = 0.015; equal variances assumed, t-test for equality of means). The number of neovessels was not significantly different between both groups (P = 0.092).Conclusion:Inhibition of mTOR was shown to reduce tumor burden, hypoxia, and vasculature in the LHBETATAG retinoblastoma tumor model. Rapamycin may have a role in combination with chemotherapy or other adjuvant therapies to enhance retinoblastoma tumor control.

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Blood Vessel Maturation in Human Uveal Melanoma: Spatial Distribution of Neovessels and Mature Vasculature

Cited by 15 publications

References 102 publications

Identification of a characteristic vascular belt zone in human colorectal cancer

Identification of a characteristic vascular belt zone in human colorectal cancer

Early SD-OCT diagnosis followed by prompt treatment of radiation maculopathy using intravitreal bevacizumab maintains functional visual acuity

Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LHBETATAG retinal tumors

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