Figure 1 (A) A schematic of ovarian cancer metastases involving tumor cells or clusters (yellow) shedding from a primary site and disseminating along ascitic currents of peritoneal fluid (green arrows) in the abdominal cavity. Ovarian cancer typically disseminates in four common abdomino-pelvic sites: (1) cul-de-sac (an extension of the peritoneal cavity between the rectum and back wall of the uterus); (2) right infracolic space (the apex formed by the termination of the small intestine of the small bowel mesentery at the ileocecal junction); (3) left infracolic space (superior site of the sigmoid colon); (4) Right paracolic gutter (communication between the upper and lower abdomen defined by the ascending colon and peritoneal wall). (B) The schematic of a perfusion model used to study the impact of sustained fluid flow on treatment resistance and molecular features of 3D ovarian cancer nodules (Top left). A side view of the perfusion model and growth of ovarian cancer nodules to a stromal bed (Top right). The photograph of a perfusion model used in the experiments (Bottom left) and depth-informed confocal imaging of ovarian cancer nodules in channels with and without carboplatin treatment (Bottom right). The perfusion model is 24 × 40 mm, with three channels that are 4 × 30 mm each and a height of 254 μm. The inlet and outlet ports of channels are 2.2 mm in diameter and positioned 5 mm from the edge of the chip. (C) A schematic of a 24-well plate model used to study the treatment resistance and molecular features of 3D ovarian cancer nodules under static conditions (without flow) (Top left). A side view of the static models and growth of ovarian cancer nodules on a stromal bed (Top right). Confocal imaging of 3D ovarian cancer nodules in a 24-well plate without and with carboplatin treatment (Bottom). Scale bars: 1 mm.

난소암에 대한 일관된 3차원 모델에서 카보플라틴에 대한 유동에 의한 전단응력변화에 관한 연구

Abstract

A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress.

전이성 난소 암과 관련된 지속적으로 암울한 통계의 주요 이유는 백금 기반 화학 요법을 포함한 기존 약제에 대한 내성 때문입니다. 치료 실패의 주요 원인은 높은 수준의 유전적 및 분자적 이질성이며, 이는 중요한 기본 게놈 불안정성과 미세 환경의 기질 및 물리적 단서로 인해 발생합니다.

난소 암은 흔히 transcoelomic 경로를 통해 먼 부위로 전파되며, 이는 악성 복수의 빈번한 생산과 가장 나쁜 예후와 관련이 있습니다. 암 성장 및 진행을위한 세포 및 단백질이 풍부한 환경을 제공하는 것 외에도 복수 액은 종양에 물리적 스트레스를 부여합니다. 난소 암 연구에서 잘 연구되지 않은 분야는 유체 전단 응력이 치료 실패에 미치는 영향입니다.

여기, 우리는 백금 기반 화학 요법에 대한 반응과 부착 3D 난소 암 결절에 대한 관류 모델에서 공격적인 질병과 관련된 분자 경로의 변조에 대한 유체 전단 응력의 효과를 조사합니다.

카르보플라틴에 대한 내성은 상피 성장 인자 수용체 (EGFR)의 발현 및 활성화의 수반되는 증가 뿐만 아니라 다운 스트림 신호 구성원인 미토겐 활성화 단백질 키나제/세포 외 신호 조절 키나제 (MEK) 및 세포 외 신호 조절과 함께 관찰됩니다. 키나아제 (ERK). 3D 난소 암 결절에 의한 백금 흡수는 정적 배양에 비해 유동 배양에서 상당히 높았습니다.

포스 포-포컬 접착 키나제 (p-FAK), 빈 쿨린 및 포스 포-팍 실린의 하향 조절은 유동 및 정적 배양 모두에서 카보 플 라틴 처리 후 관찰되었습니다. 흥미롭게도, 표적 광 화학적 양식 인 저용량 항 EGFR 광 면역 요법 (PIT)은 유동 및 정적 조건에서 성장한 난소 종양에서 똑같이 효과적인 것으로 밝혀졌습니다.

이러한 발견은 EGFR을 표적으로하는 PIT 기반 조합을 추가로 개발하고 흐름 유도 전단 응력의 맥락에서 화학 요법에 난소 암을 민감하게 할 필요성을 강조합니다.

Keywords: ovarian cancer, epidermal growth factor receptor (EGFR), mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), extracellular signal-regulated kinase (ERK), chemoresistance, fluid shear stress, ascites, perfusion model, photoimmunotherapy (PIT), photodynamic therapy (PDT), carboplatin

Figure 1 (A) A schematic of ovarian cancer metastases involving tumor cells or clusters (yellow) shedding from a primary site and disseminating along ascitic currents of peritoneal fluid (green arrows) in the abdominal cavity. Ovarian cancer typically disseminates in four common abdomino-pelvic sites: (1) cul-de-sac (an extension of the peritoneal cavity between the rectum and back wall of the uterus); (2) right infracolic space (the apex formed by the termination of the small intestine of the small bowel mesentery at the ileocecal junction); (3) left infracolic space (superior site of the sigmoid colon); (4) Right paracolic gutter (communication between the upper and lower abdomen defined by the ascending colon and peritoneal wall). (B) The schematic of a perfusion model used to study the impact of sustained fluid flow on treatment resistance and molecular features of 3D ovarian cancer nodules (Top left). A side view of the perfusion model and growth of ovarian cancer nodules to a stromal bed (Top right). The photograph of a perfusion model used in the experiments (Bottom left) and depth-informed confocal imaging of ovarian cancer nodules in channels with and without carboplatin treatment (Bottom right). The perfusion model is 24 × 40 mm, with three channels that are 4 × 30 mm each and a height of 254 μm. The inlet and outlet ports of channels are 2.2 mm in diameter and positioned 5 mm from the edge of the chip. (C) A schematic of a 24-well plate model used to study the treatment resistance and molecular features of 3D ovarian cancer nodules under static conditions (without flow) (Top left). A side view of the static models and growth of ovarian cancer nodules on a stromal bed (Top right). Confocal imaging of 3D ovarian cancer nodules in a 24-well plate without and with carboplatin treatment (Bottom). Scale bars: 1 mm.
Figure 1 (A) A schematic of ovarian cancer metastases involving tumor cells or clusters (yellow) shedding from a primary site and disseminating along ascitic currents of peritoneal fluid (green arrows) in the abdominal cavity. Ovarian cancer typically disseminates in four common abdomino-pelvic sites: (1) cul-de-sac (an extension of the peritoneal cavity between the rectum and back wall of the uterus); (2) right infracolic space (the apex formed by the termination of the small intestine of the small bowel mesentery at the ileocecal junction); (3) left infracolic space (superior site of the sigmoid colon); (4) Right paracolic gutter (communication between the upper and lower abdomen defined by the ascending colon and peritoneal wall). (B) The schematic of a perfusion model used to study the impact of sustained fluid flow on treatment resistance and molecular features of 3D ovarian cancer nodules (Top left). A side view of the perfusion model and growth of ovarian cancer nodules to a stromal bed (Top right). The photograph of a perfusion model used in the experiments (Bottom left) and depth-informed confocal imaging of ovarian cancer nodules in channels with and without carboplatin treatment (Bottom right). The perfusion model is 24 × 40 mm, with three channels that are 4 × 30 mm each and a height of 254 μm. The inlet and outlet ports of channels are 2.2 mm in diameter and positioned 5 mm from the edge of the chip. (C) A schematic of a 24-well plate model used to study the treatment resistance and molecular features of 3D ovarian cancer nodules under static conditions (without flow) (Top left). A side view of the static models and growth of ovarian cancer nodules on a stromal bed (Top right). Confocal imaging of 3D ovarian cancer nodules in a 24-well plate without and with carboplatin treatment (Bottom). Scale bars: 1 mm.
Figure 2 (A) Geometry of the micronodule located at the center of the microchannel. The flow velocity is in the X-direction. The nodule is modeled as an ellipse with a semi-minor axis of 40 μm in the Z-direction. The semi-major axis varies from 40-100 μm in the X-direction. The section over which the fluid dynamics are studied is the middle part of the channel with dimensions 4 mm along the Y-axis and 250 μm along the Z-axis. The nodule is located at (0, 20 μm). The black dotted line shows the centerline of the largest nodule. (B) Shear stress distribution over the surface of the solid micro-nodule on the XZ-plane. (C) Shear stress distribution over the surface of the porous micro-nodule on the XZ-plane. (D) Flow flux distribution over the centerline of the porous micro-nodule on the XZ-plane. The flux enters the surface at the left and leaves at the right.
Figure 2 (A) Geometry of the micronodule located at the center of the microchannel. The flow velocity is in the X-direction. The nodule is modeled as an ellipse with a semi-minor axis of 40 μm in the Z-direction. The semi-major axis varies from 40-100 μm in the X-direction. The section over which the fluid dynamics are studied is the middle part of the channel with dimensions 4 mm along the Y-axis and 250 μm along the Z-axis. The nodule is located at (0, 20 μm). The black dotted line shows the centerline of the largest nodule. (B) Shear stress distribution over the surface of the solid micro-nodule on the XZ-plane. (C) Shear stress distribution over the surface of the porous micro-nodule on the XZ-plane. (D) Flow flux distribution over the centerline of the porous micro-nodule on the XZ-plane. The flux enters the surface at the left and leaves at the right.
Figure 3 Cytotoxic response in carboplatin-treated 3D OVCAR-5 cultures under static conditions. (A) Representative confocal images of 3D tumors treated with carboplatin (0-500 μM) for 96 h showing a dose-dependent reduction in viable tumor (calcein signal). (B) Image-based quantification of normalized viable tumor area in 3D OVCAR-5 cultures following treatment with increasing doses of carboplatin. A minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was applied to the fluorescence images for quantitative analysis of the normalized viable tumor area. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; * p < 0.05; *** p < 0.001; N = 9) (C) Inductively coupled plasma mass spectrometry (ICP-MS)-based quantification of carboplatin uptake in static 3D OVCAR-5 tumors shows a dose-dependent increase in platinum levels, up to 9774 ± 3,052 ng/mg protein at an incubation concentration of 500 μM carboplatin. (One-way ANOVA with Dunn’s multiple comparisons test; n.s., not significant; * p < 0.05; ** p < 0.01; N = 3). Results are expressed as mean ± standard error of mean (SEM). Scale bars: 500 μm.
Figure 3 Cytotoxic response in carboplatin-treated 3D OVCAR-5 cultures under static conditions. (A) Representative confocal images of 3D tumors treated with carboplatin (0-500 μM) for 96 h showing a dose-dependent reduction in viable tumor (calcein signal). (B) Image-based quantification of normalized viable tumor area in 3D OVCAR-5 cultures following treatment with increasing doses of carboplatin. A minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was applied to the fluorescence images for quantitative analysis of the normalized viable tumor area. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; * p < 0.05; *** p < 0.001; N = 9) (C) Inductively coupled plasma mass spectrometry (ICP-MS)-based quantification of carboplatin uptake in static 3D OVCAR-5 tumors shows a dose-dependent increase in platinum levels, up to 9774 ± 3,052 ng/mg protein at an incubation concentration of 500 μM carboplatin. (One-way ANOVA with Dunn’s multiple comparisons test; n.s., not significant; * p < 0.05; ** p < 0.01; N = 3). Results are expressed as mean ± standard error of mean (SEM). Scale bars: 500 μm.
Figure 4 flow-induced chemo-resistance
Figure 4 flow-induced chemo-resistance
Figure 5 The effects of flow-induced shear stress on 3D ovarian cancer biology. (A) Western blot analysis of OVCAR-5 tumors was performed 7 days after culture under static or flow conditions. A flow-induced increase in EGFR and p-ERK, compared to static cultures, was observed. Conversely, a reduction in p-FAK, p-Paxillin, and Vinculin was observed under flow, relative to static conditions. (B) Western blot analysis of 3D OVCAR-5 tumors was performed 11 days after culture under static or flow conditions, including 4 days of treatment with 500 µM carboplatin, and respective controls. In both static and flow 3D cultures, carboplatin treatment resulted in downregulation of EGFR, FAK, p-Paxillin, Paxillin, and Vinculin. Upregulation of p-ERK was observed after carboplatin treatment in both static and flow 3D cultures. (C) Baseline levels of EGFR activity and expression are maintained by a complex array of factors, including recycling and degradation of the activated receptor complex. Flow-induced shear stress has been shown to cause a posttranslational up-regulation of EGFR expression and activation, likely resulting from increased receptor recycling and decreased EGFR degradation. Activation of EGFR results in ERK phosphorylation to induce gene expression, ultimately leading to cell proliferation, survival, and chemoresistance. FAK and other tyrosine kinases are activated by the engagement of integrins with the ECM. Subsequent phosphorylation of paxillin by FAK not only influences the remodeling of the actin cytoskeleton, but also modulates vinculin activation to regulate mitogen-activated protein kinase (MAPK) cascades, thereby stimulating pro-survival gene expression.
Figure 5 The effects of flow-induced shear stress on 3D ovarian cancer biology. (A) Western blot analysis of OVCAR-5 tumors was performed 7 days after culture under static or flow conditions. A flow-induced increase in EGFR and p-ERK, compared to static cultures, was observed. Conversely, a reduction in p-FAK, p-Paxillin, and Vinculin was observed under flow, relative to static conditions. (B) Western blot analysis of 3D OVCAR-5 tumors was performed 11 days after culture under static or flow conditions, including 4 days of treatment with 500 µM carboplatin, and respective controls. In both static and flow 3D cultures, carboplatin treatment resulted in downregulation of EGFR, FAK, p-Paxillin, Paxillin, and Vinculin. Upregulation of p-ERK was observed after carboplatin treatment in both static and flow 3D cultures. (C) Baseline levels of EGFR activity and expression are maintained by a complex array of factors, including recycling and degradation of the activated receptor complex. Flow-induced shear stress has been shown to cause a posttranslational up-regulation of EGFR expression and activation, likely resulting from increased receptor recycling and decreased EGFR degradation. Activation of EGFR results in ERK phosphorylation to induce gene expression, ultimately leading to cell proliferation, survival, and chemoresistance. FAK and other tyrosine kinases are activated by the engagement of integrins with the ECM. Subsequent phosphorylation of paxillin by FAK not only influences the remodeling of the actin cytoskeleton, but also modulates vinculin activation to regulate mitogen-activated protein kinase (MAPK) cascades, thereby stimulating pro-survival gene expression.
Figure 6 PIT efficacy in 3D tumors. (A) Dose-dependent change in normalized viable tumor area in static 3D cultures treated with PIC (1 μM BPD equivalent) and increasing energy densities (10–50 J/cm2 @ 50 mW/cm2). Significant tumoricidal efficacy is observed in a light-dose-dependent manner, starting at 15 J/cm2. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; ** p < 0.01, *** p < 0.001, N = 9) (B) Comparison of cytotoxic response in PIT-treated 3D cultures under static and flow conditions. For quantitative analysis of fluorescence images, a minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was used to establish normalized viable tumor area. PIT is equally effective in 3D tumors grown in static cultures (green) and under flow-induced shear stress (blue) (in contrast to flow-induced chemo-resistance shown in Figure 4) (Two-tailed t test; n.s., not significant; N = 9).
Figure 6 PIT efficacy in 3D tumors. (A) Dose-dependent change in normalized viable tumor area in static 3D cultures treated with PIC (1 μM BPD equivalent) and increasing energy densities (10–50 J/cm2 @ 50 mW/cm2). Significant tumoricidal efficacy is observed in a light-dose-dependent manner, starting at 15 J/cm2. (One-way ANOVA with Dunnett’s post hoc test; n.s., not significant; ** p < 0.01, *** p < 0.001, N = 9) (B) Comparison of cytotoxic response in PIT-treated 3D cultures under static and flow conditions. For quantitative analysis of fluorescence images, a minimum nodule size cut-off of 2000 µm2 (clusters of ~15–20 cells) was used to establish normalized viable tumor area. PIT is equally effective in 3D tumors grown in static cultures (green) and under flow-induced shear stress (blue) (in contrast to flow-induced chemo-resistance shown in Figure 4) (Two-tailed t test; n.s., not significant; N = 9).

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