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1 From the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan; the 2 Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; and the 3 Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
PURPOSE. Choroidal melanoma is the most common primary ocular cancer among the adult population. To avoid enucleation, there has been a concerted effort to develop therapies that spare the affected eye and the patient’s vision. Blood flow helps shape the tumor’s microenvironment, plays a key role in the tumor’s response to many different types of therapy, and is necessary for delivery of chemotherapeutic agents. To rationally design new therapies and optimize existing treatments, it is essential to learn as much as possible about blood flow and the microcirculation in this tumor. In recent years, much has been discovered about the anatomy of the microvasculature and the dynamics of overall blood flow in choroidal melanoma, but little is known about the factors that determine microvascular blood flow. In this study hemodynamic parameters in individual microvessels of a human choroidal melanoma xenograft were compared with those same parameters in a normal rat choroid.
METHODS. Nude, athymic WAG/RijHs-rnu rats were used in this study. The human choroidal melanoma cell line OCM-1 was used to grow solid tumors subcutaneously in the flanks of donor rats. Small pieces of these tumors were then implanted into the choroidal space of recipient rats. After 6 to 8 weeks, the rats were anesthetized with a subcutaneous injection of urethane, and the sclera was exposed. Rhodamine-labeled liposomes and red blood cells (RBCs) labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) were injected intravenously. Epifluorescent, intravital microscopy was used to visualize the flow of fluorescent RBCs through individual vessels in the choroid or tumor. Flow through multiple vessels was recorded on videotape for later analysis. From the recordings, RBC flux, RBC velocity (Vc), and microvascular hematocrit (HCTm) were determined. Similar experiments were performed in rats with no tumor growth, and these same parameters were calculated in normal choroidal vessels. RBC flow was characterized in 55 vessels in six OCM-1 tumors and in 153 choroidal vessels in five non–tumor-bearing rats.
RESULTS. RBC flux was higher in larger tumor vessels (>30 µm in diameter) compared with similarly sized choroidal vessels. There were no differences in the velocities of RBCs through the two types of vessels. HCTm was significantly higher in medium-sized (>20 µm in diameter) and larger tumor vessels compared with normal choroidal vessels.
CONCLUSIONS. These experiments demonstrate differences between hemodynamic parameters in normal choroidal microvessels and microvessels in choroidal melanoma in this animal model. Because HCTm is a key determinant of apparent viscosity, abnormally high HCTm in the tumor vessels would increase vascular resistance and decrease flow. This could have a negative impact on the tumor oxygen levels and on the ability to deliver drugs effectively. On the contrary, higher local HCTm has also been shown to increase oxygen delivery. The impact and interplay of these two effects on tumor oxygenation remain to be determined.
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