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Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy. The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.

Cancer stem cells (CSCs) play an important role during metastasis, but the dynamic behavior and induction mechanisms of CSCs are not well understood. Here, we employ high-resolution intravital microscopy using a CSC biosensor to directly observe CSCs in live mice with mammary tumors. CSCs display the slow-migratory, invadopod-rich phenotype that is the hallmark of disseminating tumor cells. CSCs are enriched near macrophages, particularly near macrophage-containing intravasation sites called Tumor Microenvironment of Metastasis (TMEM) doorways. Substantial enrichment of CSCs occurs on association with TMEM doorways, contributing to the finding that CSCs represent >60% of circulating tumor cells. Mechanistically, stemness is induced in non-stem cancer cells upon their direct contact with macrophages via Notch-Jagged signaling. In breast cancers from patients, the density of TMEM doorways correlates with the proportion of cancer cells expressing stem cell markers, indicating that in human breast cancer TMEM doorways are not only cancer cell intravasation portals but also CSC programming sites. Intravital imaging reveals macrophage-driven de novo induction of cancer stem cells in vivo, and their dramatic enrichment on dissemination through TMEM doorways. These findings provide a mechanism for the validated ability of TMEM doorway density to be prognostic for distant recurrence of metastatic tumors in breast cancer patients.

In conventional confocal microscopy, a physical pinhole is placed at the image plane prior to the detector to limit the observation volume. In this work, we present a modular design of a scanning confocal microscope which uses a CCD camera to replace the physical pinhole for materials science applications. Experimental scans were performed on a microscope resolution target, a semiconductor chip carrier, and a piece of etched silicon wafer. The data collected by the CCD were processed to yield images of the specimen. By selecting effective pixels in the recorded CCD images, a virtual pinhole is created. By analyzing the image moments of the imaging data, a lateral resolution enhancement is achieved by using a 20 × / NA = 0.4 microscope objective at 532 nm laser wavelength.

Black, compared to white, women with residual estrogen receptor-positive (ER+) breast cancer after neoadjuvant chemotherapy (NAC) have worse distant recurrence-free survival (DRFS). Such racial disparity may be due to difference in density of portals for systemic cancer cell dissemination, called TMEM doorways, and pro-metastatic tumor microenvironment (TME). Here, we evaluate residual cancer specimens after NAC from 96 Black and 87 white women. TMEM doorways are visualized by triple immunohistochemistry, and cancer stem cells by immunofluorescence for SOX9. The correlation between TMEM doorway score and pro-metastatic TME parameters with DRFS is examined using log-rank and multivariate Cox regression. Black, compared to white, patients are more likely to develop distant recurrence (49% vs 34.5%, p = 0.07), receive mastectomy (69.8% vs 54%, p = 0.04), and have higher grade tumors (p = 0.002). Tumors from Black patients have higher TMEM doorway and macrophages density overall (p = 0.002; p = 0.002, respectively) and in the ER+/HER2- (p = 0.02; p = 0.02, respectively), but not in the triple negative disease. Furthermore, high TMEM doorway score is associated with worse DRFS. TMEM doorway score is an independent prognostic factor in the entire study population (HR, 2.02; 95%CI, 1.18–3.46; p = 0.01), with a strong trend in ER+/HER2- disease (HR, 2.38; 95%CI, 0.96–5.95; p = 0.06). SOX9 expression is not associated with racial disparity in TME or outcome. In conclusion, higher TMEM doorway density in residual breast cancer after NAC is associated with higher distant recurrence risk, and Black patients are associated with higher TMEM doorway density, suggesting that TMEM doorway density may contribute to racial disparities in breast cancer.

to develop several digital pathology-based machine vision algorithms for combining TMEM and Mena scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin-fixed paraffin-embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and Mena (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and Mena . Different ways of combining TMEM doorway and Mena scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71-8.37), compared to 3.56 years (95% CI: 0.95-6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25-5.87) for the associated standalone Mena analysis. combining TMEM doorway and Mena scores as a new biomarker improves prognostication over that observed with TMEM doorway or Mena Score alone in this cohort of 86 patients.

Black women with estrogen receptor-positive, HER2-negative (ER + /HER2-) breast cancer experience higher rates of distant recurrence and worse survival outcomes compared to White women. This may be due not only to disparities in social determinants of health, but also differences in the tumor microenvironment (TME), including TMEM (Tumor Microenvironment of Metastasis) doorway score. TMEM doorways serve as portals for cancer cell hematogenous dissemination to distant sites. While higher TMEM doorway scores have been observed in Black (compared to White) patients with residual ER + /HER2- breast cancer after neoadjuvant chemotherapy, this has not been evaluated in treatment-naïve primary breast cancers. Here, we report on a multi-institutional study to evaluate TMEM doorway score in 418 treatment-naïve archived human breast cancer samples, including 265 patients with ER + /HER2-, 102 with triple negative (TNBC), and 51 with HER2-positive breast cancer. In addition to analyzing TMEM doorway scores by race across breast cancer subtypes, we examined their association with distant recurrence and assessed whether the effect of TMEM doorway scores on recurrence differed by race. Black patients had significantly higher TMEM doorway score than White patients in the overall study population (median 29.9 vs 17.9, p  < 0.001), in the ER + /HER2- (median 25.0 vs 16.8, p  < 0.001) and the HER2-positive subset (median 37.2 vs 12.9, p  = 0.003), but not in TNBC (median 36.2 vs 36.3, p  = 0.86). Racial differences in macrophage density mirrored racial differences in the TMEM doorway score. In multivariate models including age, body mass index, tumor size, grade, lymph node status, and chemotherapy treatment, neither Black race nor TMEM doorway density was associated with a higher distant recurrence risk alone. However, there was a statistically significant interaction between race and high TMEM doorway score with respect to distant recurrence risk in ER + /HER2- patients; Black patients with high TMEM doorway score were 4.6-fold (95% CI 1.28–22.82, p  = 0.03) and 4.2-fold (95% CI 1.17 – 18.23, p  = 0.04) more likely to have a distant recurrence at 5-years and 10-years, respectively, while White patients with high TMEM doorway scores did not (p = 0.21, p  = 0.11). Our study reveals racial disparities in the TME of women with ER + /HER2- breast cancer, which may play a critical role in driving disparities in breast cancer outcomes.

Purpose: to develop several digital pathology-based machine vision algorithms for combining TMEM and MenaCalc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. Methods: This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin-fixed paraffin-embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and MenaCalc (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and MenaCalc. Different ways of combining TMEM doorway and MenaCalc scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. Results: the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71–8.37), compared to 3.56 years (95% CI: 0.95–6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25–5.87) for the associated standalone MenaCalc analysis. Conclusions: combining TMEM doorway and MenaCalc scores as a new biomarker improves prognostication over that observed with TMEM doorway or MenaCalc Score alone in this cohort of 86 patients.

The photomechanical effect is the phenomenon involving any mechanical property change of a material induced by light exposure. Photomechanical devices can be built with superior performance over traditional devices and offer versatile control tactics. Previous experiments show that disperse red 1 azobenzene (DR1) doped poly(methyl methacrylate) (PMMA) optical fiber has a fast photomechanical response upon asymmetrical 633nm laser irradiation originating in photoisomerization of the dopants between the cis and trans forms, which causes an elongation of the polymer fiber. In this work, laser light of 355nm wavelength is used to investigate the dynamics of the trans to cis photoisomerization process, which should result in length contraction of the DR1 doped PMMA polymer fiber. A three-point-contact optically-actuated beam controlling tilt mount is made and used as the measurement apparatus to study this process. The photomechanical fiber is observed to elongate upon UV irradiation. Numerical simulations, which take into account the coupled effect between the laser-induced temperature increase and population density change of the dye molecules, show that contraction of the fiber due to direct trans-cis photoisomerization is overwhelmed by elongation due to the photo-thermally-stimulated cis-trans isomerization under high intensity. An ink coated entrance face of the fiber is placed in the measurement tilt mount and is found to exhibit contraction in the fast process under low intensity without sacrificing the good signal to noise ratio enjoyed in the high intensity case.

目的建立胆管细胞癌 (ICC) 常规超声特征及\"周边环状强化\"超声造影增强模式为变量的logistic回归模型,评价常规超声以及超声造影在ICC与肝细胞癌 (HCC) 鉴别诊断中的价值。方法回顾性分析55例ICC患者以及42例HCC患者的常规超声及超声造影图像特点,以手术病理或活组织检查病理为诊断金标准。评价利用logistic回归模式分析筛选出的病灶回声、血供类型、胆管扩张以及\"周边环状强化\"超声造影模式4个超声特征在ICC与HCC鉴别诊断中的价值。计量资料组间比较采用t检验;计数资料组间比较采用χ2检验。对单因素分析结果中有统计学意义的因素作为自变量再进行二分类logistic回归分析。对整个模型的拟合情况采用似然比检验,筛选出各个特征中与ICC定性诊断似然比最高者。绘制logistic回归分析模型定性诊断ICC的受试者工作特征曲线 (ROC曲线) ,计算其曲线下面积 (AUC) 。结果 2组患者在病灶回声 (χ2=4. 813,P <0. 05) 、血供类型 (χ2=10. 222,P <0. 01) 、胆管扩张 (χ...

Tumor cell intravasation is essential for metastatic dissemination, but its exact mechanism is incompletely understood. We have previously shown that in breast cancer, the direct and stable association of a tumor cell expressing Mena, a Tie2 /VEGF macrophage, and a vascular endothelial cell, creates an intravasation portal, called a \"tumor microenvironment of metastasis\" (TMEM) doorway, for tumor cell intravasation, leading to dissemination to distant sites. The density of TMEM doorways, also called TMEM doorway score, is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that tumor cells utilize TMEM doorway-associated transient vascular openings to intravasate, the precise signaling mechanisms involved in TMEM doorway function are only partially understood. Using two mouse models of breast cancer and an assay of intravasation, we report that CSF-1 secreted by the TMEM doorway tumor cell stimulates local secretion of VEGF-A from the Tie2 TMEM doorway macrophage, leading to the dissociation of endothelial junctions between TMEM doorway associated endothelial cells, supporting tumor cell intravasation. Acute blockade of CSF-1R signaling decreases macrophage VEGF-A secretion as well as TMEM doorway-associated vascular opening, tumor cell trans-endothelial migration, and dissemination. These new insights into signaling events regulating TMEM doorway function should be explored further as treatment strategies for metastatic disease.