ABSTRACT
Cancer stem cells (CSCs) are associated with the refractory nature of cancer, and elucidating the targetable pathways for CSCs is crucial for devising innovative antitumor therapies. We find that the proliferation of CSC-enriched colon spheroids from clinical specimen is dependent on mTORC1 kinase, which is activated by reactive oxygen species (ROS) produced by NOX1, an NADPH oxidase. In the spheroid-derived xenograft tumors, NOX1 is preferentially expressed in LGR5-positive cells. Dependence on NOX1 expression or mTOR kinase activity is corroborated in the xenograft tumors and mouse colon cancer-derived organoids. NOX1 co-localizes with mTORC1 in VPS41-/VPS39-positive lysosomes, where mTORC1 binds to S100A9, a member of S100 calcium binding proteins, in a NOX1-produced ROS-dependent manner. S100A9 is oxidized by NOX1-produced ROS, which facilitates binding to mTORC1 and its activation. We propose that NOX1-dependent mTORC1 activation via S100A9 oxidation in VPS41-/VPS39-positive lysosomes is crucial for colon CSC proliferation and colon cancer progression.
Subject(s)
Calgranulin B/metabolism , Colonic Neoplasms/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , NADPH Oxidase 1/metabolism , Neoplasm Proteins/metabolism , Neoplastic Stem Cells/metabolism , Animals , Calgranulin B/genetics , Colonic Neoplasms/pathology , Humans , Male , Mechanistic Target of Rapamycin Complex 1/genetics , Mice , NADPH Oxidase 1/genetics , Neoplasm Proteins/genetics , Neoplastic Stem Cells/pathology , Oxidation-ReductionABSTRACT
PURPOSE: To examine the effect of intravitreal injections of bevacizumab for myopic choroidal neovascularization (myopic CNV) that was refractory to or recurred after photodynamic therapy (PDT). METHODS: Sixteen eyes of 16 consecutive patients with myopic CNVs that were refractory to or had recurred after PDT were studied. The patients were divided into two groups; group 1 consisted of six patients whose CNV recurred after being closed by PDT, and group 2 consisted of ten patients whose CNV did not respond to an earlier treatment. All of the eyes were injected intravitreally with 1.25 mg bevacizumab. The best-corrected visual acuity (BCVA) and fluorescein angiograms (FA) were assessed in both groups. RESULTS: The mean follow-up period was 15.1 +/- 3.6 months. Patients received a mean of 1.8 +/- 0.8 injections. The mean BCVA in the 16 patients at the final visit was significantly improved over that before the injection. Dye leakage had disappeared in 83.3% of group 1, and in all of the eyes of group 2 at the final visit. CONCLUSIONS: Intravitreal bevacizumab is effective for myopic CNVs that were either refractory to PDT or had recurred after being regressed by PDT.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Choroidal Neovascularization/drug therapy , Myopia, Degenerative/complications , Photochemotherapy , Adult , Aged , Antibodies, Monoclonal, Humanized , Bevacizumab , Choroidal Neovascularization/etiology , Choroidal Neovascularization/physiopathology , Female , Fluorescein Angiography , Follow-Up Studies , Humans , Injections , Male , Middle Aged , Prospective Studies , Recurrence , Treatment Outcome , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Visual Acuity/physiology , Vitreous BodyABSTRACT
PURPOSE: To examine the effects of photodynamic therapy (PDT) with verteporfin on subfoveal or juxtafoveal choroidal neovascularization (CNV) secondary to pathologic myopia in Japanese patients and to compare the visual outcomes of PDT-treated patients with that of age-matched and visual acuity-matched untreated controls. DESIGN: Prospective, open-label, consecutive, interventional case series. METHODS: We prospectively followed up 43 eyes of 42 consecutive patients with pathologic myopia (>6 diopters or axial length>26.5 mm) who received PDT for myopic CNV. In addition, the visual outcomes of these patients who were followed up for more than one year were compared with those of age- and initial visual acuity-matched untreated controls. RESULTS: The average follow-up was 15.0+/-7.0 months. Patients received an average of 1.40+/-0.73 treatments during follow-up, and 30 eyes (69.8%) required only one treatment. The best-corrected visual acuity (BCVA) improved by more than two Snellen lines in seven eyes (16.3%), decreased in six eyes (14.0%), and remained stable in 30 eyes (69.7%). In three eyes with a juxtafoveal CNV, CNV could not be detected ophthalmoscopically or angiographically after PDT. Statistical analysis showed that the PDT-treated patients had significantly better visual acuity at one year after PDT than the age- and initial BCVA-matched untreated controls. CONCLUSIONS: These results indicate that PDT was beneficial for maintaining vision in Japanese patients with myopic CNV. The visual outcome after PDT was better than the natural course of the disease as determined from untreated controls. The effect on chorioretinal atrophy around CNV should be investigated with a long-term study.
