In vivo quantification of the structural changes of collagens and tumor angiogenesis permeability in the melanoma microenvironment with nonlinear optical microscopy
Date Issued
2015
Date
2015
Author(s)
Wu, Pei-Chun
Abstract
Malignant neoplasm is the leading cause of death for 30 years in a row in Taiwan. The major approaches for cancer treatment are surgery, chemotherapy, and radiation therapy, but these approaches not only can hurt all kinds of cancers but also do harm to the normal cells. In order to kill cancer cells specifically, targeted therapy is developed. Many researchers focused on the tumor microenvironment as a target for cancer treatment recently and they found it would be an effective and potential target. The goal of this thesis is to investigate the relationship between collagen remodeling, angiogenesis, vessel permeability and cancer stem cells (CSC) in the microenvironment of melanoma. In tumor microenvironment, the collagen fibers in normal tissues play a role in the regulation of cell communication. Recent studies found collagen fibers surrounding cancer cells may regulate cancer metastasis, indicating collagen fibers might be used as indicators for cancer prognosis. We tracked the collagen remodeling in melanoma microenvironment by using in vivo second harmonic generation (SHG) and third harmonic generation (THG) microscopy. The corresponding structural and morphological changes of collagen were quantitatively analyzed without labeling using an orientation index (OI), the gray level co-occurrence matrix (GLCM) method, and the intensity ratio of THG to SHG (RTHG/SHG). We found that collagen fibers surrounding melanoma cells had higher OI values and SHG intensities initially after implantation of melanoma cells, and these collagen networks had lower OI values and less homogeneity following the growth of tumors. To investigate the roles of melanoma CSC and the vessel permeability, we implanted the mCherry and ALDH1A1 regulatory element–driven EGFP melanoma cells into C57BL/6-c2J mice ears. The 150-kDa (the radius is about 8.9 nm) dextran labeled with fluorescein were injected via tail veins of mice with different tumor sizes. We found that the tumor region enriched with melanoma CSC correlates with higher vessel permeability. Besides, we observed that vessels with increased permeability were mainly arterioles and the density of neoangiogenesis was related to tumor growth.
Subjects
nonlinear optical microscopy
melanoma microenvironment
melanoma stem cells
collagen remodeling
angiogenesis
vessel permeability.
SDGs
Type
thesis
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