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Bolat Kucukzeybek B, Dere Y, Akder Sari A, Ocal I, Avcu E, Dere O, Orgen Calli A, Dinckal C, Tunakan M, Kucukzeybek Y. The prognostic significance of CD117-positive mast cells and microvessel density in colorectal cancer. Medicine (Baltimore) 2024; 103:e38997. [PMID: 39029054 PMCID: PMC11398830 DOI: 10.1097/md.0000000000038997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/28/2024] [Indexed: 07/21/2024] Open
Abstract
The prognostic significance of angiogenesis has been demonstrated in various types of cancer. However, in colorectal cancer (CRC), there are conflicting results regarding the relationship between angiogenesis and clinical-histopathological prognostic factors. Mast cells are immune system cells found in the inflammatory microenvironment; their role in carcinogenesis and prognosis remains unclear although they are considered to cause cancer development and progression. The present study aims to evaluate the prognostic significance of mast cell accumulation and angiogenesis assessed by microvessel density (MVD) in patients with CRC. Patients who underwent curative resection and who were not treated with neoadjuvant chemotherapy were included. The anti-CD34 antibody and anti-CD117 antibody were utilized for the immunohistochemical assessment of MVD and the mast cell count (MCC) in the tissue samples, respectively. The relationship between MCC, MVD, survival and clinical-histopathological prognostic factors were evaluated. A total of 94 patients were enrolled to the study. In a median 49-month follow-up, 65 patients (69.1%) died. The 5-year disease-free survival was 61.1% and 31.3% for the group with CD34 < 18.3% and CD34 > 18.3%, respectively (P = .001). The same groups presented 5-year overall survival rates of 77, 1% and 51, 4%, respectively (P, .012). The MVD was found to be associated with the pathological T stage, lymph node metastasis and distant metastasis (P < .05). Although the MCC was positively correlated with MVD, there was no association between the MCC and clinical-histopathological prognostic factors. MVD-assessed angiogenesis was significantly related to survival and the clinical-histopathological prognostic factors in patients diagnosed with CRC.
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Affiliation(s)
- Betul Bolat Kucukzeybek
- Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Yelda Dere
- Department of Pathology, Mugla Sitki Kocman University, Faculty of Medicine, Mugla, Turkey
| | - Aysegul Akder Sari
- Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Irfan Ocal
- Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Emel Avcu
- Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Ozcan Dere
- Department of Surgery, Mugla Sitki Kocman University, Faculty of Medicine, Mugla, Turkey
| | - Aylin Orgen Calli
- Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Cigdem Dinckal
- Department of Medical Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Mine Tunakan
- Department of Pathology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Yuksel Kucukzeybek
- Department of Medical Oncology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
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Sun Q, Bian X, Sun D, Wang M, Dong H, Dai X, Fan G, Zhang L, Li Y, Chen G. The value of preoperative diagnosis of colorectal adenocarcinoma pathological T staging based on dual-layer spectral-detector computed tomography extracellular volume fraction: a preliminary study. Jpn J Radiol 2024; 42:612-621. [PMID: 38381249 DOI: 10.1007/s11604-024-01537-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 01/18/2024] [Indexed: 02/22/2024]
Abstract
PURPOSE To investigate the value of preoperative diagnosis of colorectal adenocarcinoma (CRAC) pathological T staging based on dual-layer spectral-detector computed tomography (DLCT) extracellular volume fraction (ECV) of CRAC lesions. METHODS We prospectively collected clinical and DLCT imaging data from 165 patients with CRAC who attended two hospitals from June 2022 to April 2023. The enrolled patients were divided into a training group (n = 110, from Hospital 1) and an external validation group (n = 55, from Hospital 2). Measuring and calculating DLCT parameters of lesions, including CT values of 40 and 100 keV virtual mono-energetic images (VMI), iodine concentration (IC) and effective atomic number (Eff-Z) in the arterial phases (AP) and venous phases (VP), and ECV in the delayed phase (DP). The differences in clinical characteristics and DLCT parameters were compared between different pT subgroups. The correlation between DLCT parameters and pT stages were evaluated by Spearman correlation analysis. A multifactorial binary logistic stepwise forward regression analysis was performed to obtain independent influences associated with pT stage. Receiver operating characteristic curves (ROCs) were used to assess diagnostic efficacy and were expressed as area under the curve (AUC). RESULTS Each DLCT parameter was higher in pT3 stage tumors than in pT1-2 stage tumors (all P < 0.05). The highest correlation was found between ECV and pT stage (r = 0.637). ECV were independent influences associated with pT stage. ECV had excellent diagnostic efficacy for CRAC pT staging in both the training and external validation groups (AUC = 0.919 and 0.892). CONCLUSION ECV based on DLCT measurement can be used for preoperative noninvasive diagnosis of CRAC pT staging with excellent diagnostic efficacy. It can provide a new imaging marker for the preoperative evaluation of CRAC and help clinicians formulate individualized treatment earlier. However, it needs to be confirmed with a larger sample size.
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Affiliation(s)
- Qi Sun
- Department of Radiology, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China
| | - Xuelian Bian
- Department of Radiology, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China
| | - Danqi Sun
- Department of Radiology, First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, 215004, Jiangsu, China
| | - Mi Wang
- Department of Radiology, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China
| | - Hanyun Dong
- Department of Radiology, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China
| | - Xiaoxiao Dai
- Department of Pathology, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China
| | - Guohua Fan
- Department of Radiology, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China
| | - Liyuan Zhang
- Department of Radiotherapy, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China
| | - Yonggang Li
- Department of Radiology, First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou, 215004, Jiangsu, China
| | - Guangqiang Chen
- Department of Radiology, Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, Jiangsu, China.
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Yang J, Shu G, Chen T, Dong A, Dong C, Li W, Sun X, Zhou Y, Li D, Zhou J. ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis. Cancers (Basel) 2023; 16:194. [PMID: 38201620 PMCID: PMC10778290 DOI: 10.3390/cancers16010194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/22/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1α, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Dongbao Li
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; (J.Y.); (G.S.); (T.C.); (A.D.); (C.D.); (W.L.); (X.S.); (Y.Z.)
| | - Jin Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China; (J.Y.); (G.S.); (T.C.); (A.D.); (C.D.); (W.L.); (X.S.); (Y.Z.)
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Pandey S, Shukla S, Vagha S. Utility of CD34 in Assessing Microvessel Density and Its Correlation With Clinicopathological Parameters in Colorectal Carcinoma Patients. Cureus 2023; 15:e49186. [PMID: 38130549 PMCID: PMC10734711 DOI: 10.7759/cureus.49186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023] Open
Abstract
Currently, the most commonly practiced method of reporting cases of colorectal carcinoma is done according to guidelines provided by the College of American Pathologists (8th edition) and the Royal College of Pathologists (UK). These guidelines include various histopathological parameters like tumor site, extent, histologic type, grade, margins, tumor budding, lymphovascular invasion, and perineural invasion. However, in the present guidelines, the immunohistochemistry-based marker of mean vessel density (MVD) has not been addressed as an important parameter. The present study gives an overview of the importance of MVD. MVD was statistically significant when correlated with tumor size, lymph node metastasis, grade, and vascular invasion. However, no statistical significance was observed when compared with age, perineural invasion, and stage of the tumor.
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Affiliation(s)
- Shweta Pandey
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Samarth Shukla
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Sunita Vagha
- Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Sotra A, Jozani KA, Zhang B. A vascularized crypt-patterned colon model for high-throughput drug screening and disease modelling. LAB ON A CHIP 2023. [PMID: 37335565 DOI: 10.1039/d3lc00211j] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2023]
Abstract
The colon serves as a primary target for pharmaceutical compound screening and disease modelling. To better study colon diseases and develop treatments, engineered in vitro models with colon-specific physiological features are required. Existing colon models lack integration of colonic crypt structures with underlying perfusable vasculature, where vascular-epithelial crosstalk is affected by disease progression. We present a colon epithelium barrier model with vascularized crypts that recapitulates relevant cytokine gradients in both healthy and inflammatory conditions. Using our previously published IFlowPlate384 platform, we initially imprinted crypt topography and populated the patterned scaffold with colon cells. Proliferative colon cells spontaneously localized to the crypt niche and differentiated into epithelial barriers with a tight brush border. Toxicity of the colon cancer drug, capecitabine, was tested and showed a dose-dependent response and recovery from crypt-patterned colon epithelium exclusively. Perfusable microvasculature was then incorporated around the colon crypts followed by treatment with pro-inflammatory TNFα and IFNγ cytokines to simulate inflammatory bowel disease (IBD)-like conditions. We observed in vivo-like stromal basal-to-apical cytokine gradients in tissues with vascularized crypts and gradient reversals upon inflammation. Taken together, we demonstrated crypt topography integrated with underlying perfusable microvasculature has significant value for emulating colon physiology and in advanced disease modelling.
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Affiliation(s)
- Alexander Sotra
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
| | - Kimia Asadi Jozani
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
| | - Boyang Zhang
- School of Biomedical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada.
- Department of Chemical Engineering, McMaster University, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
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Wang L, Yuan PQ, Taché Y. Vasculature in the mouse colon and spatial relationships with the enteric nervous system, glia, and immune cells. Front Neuroanat 2023; 17:1130169. [PMID: 37332321 PMCID: PMC10272736 DOI: 10.3389/fnana.2023.1130169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/15/2023] [Indexed: 06/20/2023] Open
Abstract
The distribution, morphology, and innervation of vasculature in different mouse colonic segments and layers, as well as spatial relationships of the vasculature with the enteric plexuses, glia, and macrophages are far from being complete. The vessels in the adult mouse colon were stained by the cardiovascular perfusion of wheat germ agglutinin (WGA)-Alexa Fluor 448 and by CD31 immunoreactivity. Nerve fibers, enteric glia, and macrophages were immunostained in the WGA-perfused colon. The blood vessels entered from the mesentery to the submucosa and branched into the capillary networks in the mucosa and muscularis externa. The capillary net formed anastomosed rings at the orifices of mucosa crypts, and the capillary rings surrounded the crypts individually in the proximal colon and more than two crypts in the distal colon. Microvessels in the muscularis externa with myenteric plexus were less dense than in the mucosa and formed loops. In the circular smooth muscle layer, microvessels were distributed in the proximal, but not the distal colon. Capillaries did not enter the enteric ganglia. There were no significant differences in microvascular volume per tissue volume between the proximal and distal colon either in the mucosa or muscularis externa containing the myenteric plexus. PGP9.5-, tyrosine hydroxylase-, and calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers were distributed along the vessels in the submucosa. In the mucosa, PGP9.5-, CGRP-, and vasoactive intestinal peptide (VIP)-immunoreactive nerves terminated close to the capillary rings, while cells and processes labeled by S100B and glial fibrillary acidic protein were distributed mainly in the lamina propria and lower portion of the mucosa. Dense Iba1 immunoreactive macrophages were closely adjacent to the mucosal capillary rings. There were a few macrophages, but no glia in apposition to microvessels in the submucosa and muscularis externa. In conclusion, in the mouse colon, (1) the differences in vasculature between the proximal and distal colon were associated with the morphology, but not the microvascular amount per tissue volume in the mucosa and muscle layers; (2) the colonic mucosa contained significantly more microvessels than the muscularis externa; and (3) there were more CGRP and VIP nerve fibers found close to microvessels in the mucosa and submucosa than in the muscle layers.
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Affiliation(s)
- Lixin Wang
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Pu-Qing Yuan
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Yvette Taché
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
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Li Q, Bao J, Zhang Y, Dou Y, Liu A, Liu M, Wu H, Wu J, Zhao L, Yang Z, Zhu L, Gao W, Zhao W, Wei M, Hao F. Predictive value of CT-based extracellular volume fraction in the preoperative pathologic grading of rectal adenocarcinoma: A preliminary study. Eur J Radiol 2023; 163:110811. [PMID: 37062204 DOI: 10.1016/j.ejrad.2023.110811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/18/2023]
Abstract
OBJECTIVE This study aimed to investigate whether the extracellular volume fraction (ECV) determined using enhanced computed tomography (CT) can predict the pathologic grade of rectal adenocarcinoma. METHODS We prospectively analyzed 43 patients with rectal adenocarcinoma confirmed surgically and pathologically and who had undergone preoperative enhanced CT imaging. The plain, arterial, venous, and balance phase values were recorded, and the absolute contrast-enhanced CT differences ΔS1 = HUarterial phase-HUplain scan, ΔS2 = HUvenous phase-HUplain scan, ΔS3 = HUbalance phase-HUplain scan were obtained. The ECV of the primary lesion was calculated by measuring the CT values of the regions of interest in the plain and balance phases. Patients were allocated to either a low-grade or a high-grade group based on the histologic grading standard for colorectal adenocarcinoma (nonspecial type, World Health Organization 2010 standard). The differences in the parameters between the two groups were evaluated for statistical significance. A receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficiency. RESULTS The 43 enrolled patients [12 in the high-grade group (27.9%) and 31 in the low-grade group (72.1%)] had an average age of 64.47 years. The arterial phase (P = 0.005) as well as ΔS1 (P = 0.006), ΔS3 (P = 0.021), and ECV (P＜ 0.001) differed significantly between the high-grade and low-grade groups, with ECV (P＜ 0.001) and ΔS3 (P = 0.042) being positively correlated with the pathologic grade and arterial phase (P = 0.025) and ΔS1 (P = 0.005) being negatively correlated. The ROC curve demonstrated that the best efficacy in evaluating the pathologic grade of rectal cancer was achieved by ECV, with an area under the curve of 0.892 (95% confidence interval: 0.757-1.000). The diagnostic threshold was 34.42%, sensitivity was 91.7%, and specificity was 83.9%. CONCLUSION The use of enhanced CT to obtain ECV is helpful in predicting the pathologic grade of rectal cancer; however, this result has to be confirmed in a study with a larger sample size.
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Affiliation(s)
- Qingyang Li
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Jiaqi Bao
- Department of Oncology, Inner Mongolia Autonomous Region People's Hospital, Hohhot 010020, China
| | - Yuqi Zhang
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Yana Dou
- Computed Tomography System Division, Siemens Medical Systems Ltd, Beijing 100102, China
| | - Aishi Liu
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Miaomiao Liu
- Department of Radiology, Shaw Hospital Affiliated to Zhejiang University, Hangzhou 310016, China
| | - Hui Wu
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Jing Wu
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Lei Zhao
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Zhenxing Yang
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Lu Zhu
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Wei Gao
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Wei Zhao
- Department of Radiology, Linfen People's Hospital, Shanxi 041000, China
| | - Mingjie Wei
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China
| | - Fene Hao
- Department of Radiology, The Affiliated Hospital of Inner Mongolia Medical University, Huhhot 010050, China.
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Chen W, Ye Y, Zhang D, Mao L, Guo L, Zhang H, Du X, Deng W, Liu B, Liu X. Utility of dual-layer spectral-detector CT imaging for predicting pathological tumor stages and histologic grades of colorectal adenocarcinoma. Front Oncol 2022; 12:1002592. [PMID: 36248968 PMCID: PMC9564703 DOI: 10.3389/fonc.2022.1002592] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/09/2022] [Indexed: 11/13/2022] Open
Abstract
Objectives To assess the utility of Dual-layer spectral-detector CT (DLCT) in predicting the pT stage and histologic grade for colorectal adenocarcinoma (CRAC). Methods A total of 131 patients (mean 62.7 ± 12.9 years; 72 female, 59 male) with pathologically confirmed CRAC (35 pT1-2, 61 pT3, and 35 pT4; 32 high grade and 99 low grade), who received dual-phase DLCT were enrolled in this retrospective study. Normalized iodine concentration (NIC), slope of the spectral HU curve (λHU), and effective atomic number (Eff-Z) were measured for each lesion by two radiologists independently. Intraobserver reliability and interobserver agreement were assessed. The above values were compared between three pT-stage and two histologic-grade groups. The correlation between the pT stages and above values were assessed. Receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic efficacy. Results Intra-class correlation coefficients were ranged from 0.856 to 0.983 for all measurements. Eff-Z [7.21(0.09) vs 7.31 (0.10) vs 7.35 (0.19)], NICAP [0.11 (0.05) vs 0.15 (0.08) vs 0.15 (0.08)], NICVP [0.27 (0.06) vs 0.34 (0.11) vs 0.35 (0.12)], λHUAP [1.20 (0.45) vs 1.93 (1.18) vs 2.37 (0.91)], and λHUVP [2.07 (0.68) vs 2.35 (0.62) vs 3.09 (1.07)] were significantly different among pT stage groups (all P<0.001) and exhibited a positive correlation with pT stages (r= 0.503, 0.455, 0.394, 0.512, 0.376, respectively, all P<0.001). Eff-Z [7.37 (0.10) vs 7.28 (0.08)], NICAP[0.20 (0.10) vs 0.13 (0.08)], NICVP[0.35 (0.07) vs 0.31 (0.11)], and λHUAP [2.59 (1.11) vs 1.63 (0.75)] in the high-grade group were markedly higher than those in the low-grade group (all P<0.05). For discriminating the advanced- from early-stage CARC, the AUCs of Eff-Z, NICAP, NICVP, λHUAP, and λHUVP were 0.83, 0.80, 0.79, 0.86, and 0.68, respectively (all P<0.001). For discriminating the high- from low-grade CARC, the AUCs of Eff-Z, NICAP, NICVP, and λHUAP were 0.81, 0.81, 0.64, and 0.81, respectively (all P<0.05). Conclusions The quantitative parameters derived from DLCT may provide new markers for assessing pT stages and histologic differentiation in patients with CRAC.
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Affiliation(s)
- Weicui Chen
- Department of Radiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yongsong Ye
- Department of Radiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Daochun Zhang
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, China
| | - Liting Mao
- Department of Radiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Guo
- Department of Radiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hanliang Zhang
- Department of Radiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaohua Du
- Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Weiwei Deng
- Clinical and Technical Support, Philips Healthcare, Shanghai, China
| | - Bo Liu
- Department of Radiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xian Liu
- Department of Radiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Xian Liu,
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9
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Chakroborty D, Goswami S, Fan H, Frankel WL, Basu S, Sarkar C. Neuropeptide Y, a paracrine factor secreted by cancer cells, is an independent regulator of angiogenesis in colon cancer. Br J Cancer 2022; 127:1440-1449. [PMID: 35902640 PMCID: PMC9553928 DOI: 10.1038/s41416-022-01916-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Resistance to anti-angiogenic therapies targeting vascular endothelial growth factor-A (VEGF-A) stems from VEGF-A independent angiogenesis mediated by other proangiogenic factors. Therefore identifying these factors in colon adenocarcinoma (CA) will reveal new therapeutic targets. METHODS Neuropeptide Y (NPY) and Y2 receptor (Y2R) expressions in CA were studied by immunohistochemical analysis. Orthotopic HT29 with intact VEGF-A gene and VEGF-A knockdown (by CRISPR/Cas9 gene-editing technique) HT29 colon cancer-bearing mice were treated with specific Y2R antagonists, and the effects on angiogenesis and tumour growth were studied. The direct effect of NPY on angiogenesis and the underlying molecular mechanism was elucidated by the modulation of Y2R receptors expressed on colonic endothelial cells (CEC). RESULTS The results demonstrated that NPY and Y2R are overexpressed in human CA, orthotopic HT29, and most interestingly in VEGF-A-depleted orthotopic HT29 tumours. Treatment with Y2R antagonists inhibited angiogenesis and thereby HT29 tumour growth. Blocking /silencing Y2R abrogated NPY-induced angiogenic potential of CEC. Mechanistically, NPY regulated the activation of the ERK/MAPK signalling pathway in CEC. CONCLUSIONS NPY derived from cancer cells independently regulates angiogenesis in CA by acting through Y2R present on CEC. Targeting NPY/Y2R thus emerges as a novel potential therapeutic strategy in CA.
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Affiliation(s)
- Debanjan Chakroborty
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.,Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA.,Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA
| | - Sandeep Goswami
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA.,Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA
| | - Hao Fan
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA
| | - Wendy L Frankel
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA
| | - Sujit Basu
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA.,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.,Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Chandrani Sarkar
- Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA. .,Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. .,Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA. .,Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA. .,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA.
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10
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Uil SH, Coupé VMH, Bril H, Meijer GA, Fijneman RJA, Stockmann HBAC. KCNQ1 and lymphovascular invasion are key features in a prognostic classifier for stage II and III colon cancer. BMC Cancer 2022; 22:372. [PMID: 35395779 PMCID: PMC8991490 DOI: 10.1186/s12885-022-09473-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 03/24/2022] [Indexed: 12/15/2022] Open
Abstract
Background The risk of recurrence after resection of a stage II or III colon cancer, and therefore qualification for adjuvant chemotherapy (ACT), is traditionally based on clinicopathological parameters. However, the parameters used in clinical practice are not able to accurately identify all patients with or without minimal residual disease. Some patients considered ‘low-risk’ do develop recurrence (undertreatment), whilst other patients receiving ACT might not have developed recurrence at all (overtreatment). We previously analysed tumour tissue expression of 28 protein biomarkers that might improve identification of patients at risk of recurrence. In the present study we aimed to build a prognostic classifier based on these 28 biomarkers and clinicopathological parameters. Methods Classification and regression tree (CART) analysis was used to build a prognostic classifier based on a well described cohort of 386 patients with stage II and III colon cancer. Separate classifiers were built for patients who were or were not treated with ACT. Routine clinicopathological parameters and tumour tissue immunohistochemistry data were included, available for 28 proteins previously published. Classification trees were pruned until lowest misclassification error was obtained. Survival of the identified subgroups was analysed, and robustness of the selected CART variables was assessed by random forest analysis (1000 trees). Results In patients not treated with ACT, prognosis was estimated best based on expression of KCNQ1. Poor disease-free survival (DFS) was observed in those with loss of expression of KCNQ1 (HR = 3.38 (95% CI 2.12 – 5.40); p < 0.001). In patients treated with ACT, key prognostic factors were lymphovascular invasion (LVI) and expression of KCNQ1. Patients with LVI showed poorest DFS, whilst patients without LVI and high expression of KCNQ1 showed most favourable survival (HR = 7.50 (95% CI 3.57—15.74); p < 0.001). Patients without LVI and loss of expression of KCNQ1 had intermediate survival (HR = 3.91 (95% CI 1.76 – 8.72); p = 0.001). Conclusion KCNQ1 and LVI were identified as key features in prognostic classifiers for disease-free survival in stage II and III colon cancer patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09473-9.
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Affiliation(s)
- Sjoerd H Uil
- Department of Surgery, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC, Haarlem, The Netherlands
| | - Veerle M H Coupé
- Department of Epidemiology and Data Science, Amsterdam University Medical Center, de Boelelaan 1089a, 1081 HV, Amsterdam, The Netherlands
| | - Herman Bril
- Department of Pathology, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC, Haarlem, The Netherlands
| | - Gerrit A Meijer
- Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Remond J A Fijneman
- Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
| | - Hein B A C Stockmann
- Department of Surgery, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC, Haarlem, The Netherlands
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11
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Kampoli K, Foukas PG, Ntavatzikos A, Arkadopoulos N, Koumarianou A. Interrogating the interplay of angiogenesis and immunity in metastatic colorectal cancer. World J Methodol 2022; 12:43-53. [PMID: 35117981 PMCID: PMC8790311 DOI: 10.5662/wjm.v12.i1.43] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 08/17/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
Colon cancer is the third most common malignancy and the fifth most frequent cause of death from neoplastic disease worldwide. At the time of diagnosis, more than 20% of patients already have metastatic disease. In the last 20 years, the natural course of the disease has changed due to major changes in the management of metastatic disease such as the advent of novel surgical and local therapy approaches as well as the introduction of novel chemotherapy drugs and targeted agents such as anti-epidermal growth factor receptor, anti-BRAF and antiangiogenics. Angiogenesis is a complex biological process of new vessel formation from existing ones and is an integral component of tumor progression supporting cancer cells to grow, proliferate and metastasize. Many molecules are involved in this proangiogenic process, such as vascular endothelial growth factor and its receptors on endothelial cells. A well-standardized methodology that is applied to assess angiogenesis in the tumor microenvironment is microvascular density by using immunohistochemistry with antibodies against endothelial CD31, CD34 and CD105 antigens. Even smaller molecules, such as the microRNAs, which are small non-coding RNAs, are being studied for their usefulness as surrogate biomarkers of angiogenesis and prognosis. In this review, we will discuss recent advances regarding the investigation of angiogenesis, the crosstalk between elements of the immune microenvironment and angiogenesis and how a disorganized tumor vessel network affects the trafficking of CD8+ T cells in the tumor bed. Furthermore, we will present recent data from clinical trials that combine antiangiogenic therapies with immune checkpoint inhibitors in colorectal cancer.
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Affiliation(s)
- Katerina Kampoli
- Hematology Oncology Unit, The Fourth Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Periklis G Foukas
- The Second Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Anastasios Ntavatzikos
- Hematology Oncology Unit, The Fourth Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Nikolaos Arkadopoulos
- The Fourth Surgical Clinic, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
| | - Anna Koumarianou
- Hematology Oncology Unit, The Fourth Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Haidari 12462, Athens, Greece
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12
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The Concentration of CMKLR1 Expression on Clinicopathological Parameters of Colorectal Cancer: A Preliminary Study. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57121299. [PMID: 34946244 PMCID: PMC8708422 DOI: 10.3390/medicina57121299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 12/13/2022]
Abstract
Background and Objectives: Colorectal cancer (CRC) is the second-most common cause of cancer-related deaths worldwide. Angiogenesis is crucial for cancer growth, infiltration of surrounding tissues, and metastasis and plays a key role in the pathogenesis of CRC. Chemerin/chemokine-like receptor 1 (CMKLR1) is one of the biochemical pathways involved in the regulation of angiogenesis in solid tumors. The aim of the study was to assess the CMKLR1 level in tumor and margin tissues of CRC in relation to histopathological parameters: microvessel density (MVD), budding, tumor-infiltrating lymphocytes (TILs), TNM scale, and grading. Materials and Methods: The study involved 43 samples of tumor and margin tissues obtained from CRC patients. To assess the concentration of CMKLR1 a commercially available enzyme-linked immunosorbent assay kit was used. For 35 cases, we performed CD34 immunostaining. The MVD, budding, and TILs were assessed using a light microscope. Results: The levels of CMKLR1 in both tumor and margin were negatively correlated with MVD and budding. CMKLR1 concentration in margin was higher in tissues with lymphocytic infiltration. Conclusions: Low vascularity and low budding are associated with higher CMKLR1 expression. CMKLR1 might play a multifunctional role in CRC pathogenesis by influencing tumor budding and peritumoral lymphocytic infiltration.
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13
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Guo X, Meng X, Liu R. Prognostic value of microvessel density in esophageal squamous cell carcinoma-a systematic review and meta-analysis. Pathol Res Pract 2021; 227:153644. [PMID: 34634564 DOI: 10.1016/j.prp.2021.153644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Angiogenesis produced by tumor microenvironment is play an important role in development of esophageal squamous cell carcinoma (ESCC). As a quantitative index of angiogenesis, literature has emerged contradictory results about the prognostic role of microvessel density (MVD) in ESCC. The aim of the study was to explore the impact of the correlation between MVD and the prognosis of ESCC based the published evidence. METHODS Pubmed and Web of science database were screened for the relationship of MVD with prognostic feature in ESCC up to March, 2021. 11 relevant articles were used for meta-analysis. The following data were extracted from the literature: author, year, country, the patients number of high/low MVD, tumor-node-metastasis (TNM) classification, clinical stage, lymphoid infiltrates, vessel invasion, invasive depth, differential degree and survival rate. The hazard ratio (HR) and odds ratios (OR) with 95% CI were used to assess the associations between MVD and overall survival (OS). Chi-squared test and I2 statistics were completed to evaluate the heterogeneity in our study. A random-effects model was used when significant heterogeneity existed (I2>50% and p < 0.05). Egger test was used to calculate the publication bias. Subgroup analysis was stratified by antibody, region, sample capacity to explore the source of heterogeneity. RESULTS 11 studies with 1055 patients were analyzed. Our results suggested that high MVD is an important factor to advanced TNM classification and clinical stage, and the high MVD is positive correlation with the lymph node invasion and vascular invasion(p < 0.05) in ESCC, but irrelevant to poor differential and invasive depth(p > 0.05). The result also indicated that low MVD is a benefit factor to prolong the survival rate (p < 0.05). And the source of the heterogeneity maybe is that the antibody used to detect the MVD was not consistent, patient number was not large enough and the count method on MVD. CONCLUSION Across multiple studies, high MVD is correlated with clinicopathological criteria of poor prognosis and survival in ESCC. MVD could be the quantitative index to reactive angiogenesis and may play a pivotal role in ESCC development and progression. MVD may represent a valuable addition to current pathologic analysis and help to guide prognosis and treatment.
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Affiliation(s)
- Xinxin Guo
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Xingchen Meng
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
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Mungenast F, Fernando A, Nica R, Boghiu B, Lungu B, Batra J, Ecker RC. Next-Generation Digital Histopathology of the Tumor Microenvironment. Genes (Basel) 2021; 12:538. [PMID: 33917241 PMCID: PMC8068063 DOI: 10.3390/genes12040538] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/30/2021] [Accepted: 04/01/2021] [Indexed: 12/11/2022] Open
Abstract
Progress in cancer research is substantially dependent on innovative technologies that permit a concerted analysis of the tumor microenvironment and the cellular phenotypes resulting from somatic mutations and post-translational modifications. In view of a large number of genes, multiplied by differential splicing as well as post-translational protein modifications, the ability to identify and quantify the actual phenotypes of individual cell populations in situ, i.e., in their tissue environment, has become a prerequisite for understanding tumorigenesis and cancer progression. The need for quantitative analyses has led to a renaissance of optical instruments and imaging techniques. With the emergence of precision medicine, automated analysis of a constantly increasing number of cellular markers and their measurement in spatial context have become increasingly necessary to understand the molecular mechanisms that lead to different pathways of disease progression in individual patients. In this review, we summarize the joint effort that academia and industry have undertaken to establish methods and protocols for molecular profiling and immunophenotyping of cancer tissues for next-generation digital histopathology-which is characterized by the use of whole-slide imaging (brightfield, widefield fluorescence, confocal, multispectral, and/or multiplexing technologies) combined with state-of-the-art image cytometry and advanced methods for machine and deep learning.
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Affiliation(s)
- Felicitas Mungenast
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
- TissueGnostics GmbH, 1020 Vienna, Austria;
| | - Achala Fernando
- Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Australia; (A.F.); (J.B.)
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia
| | | | - Bogdan Boghiu
- TissueGnostics SRL, 700028 Iasi, Romania; (B.B.); (B.L.)
| | - Bianca Lungu
- TissueGnostics SRL, 700028 Iasi, Romania; (B.B.); (B.L.)
| | - Jyotsna Batra
- Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Australia; (A.F.); (J.B.)
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia
| | - Rupert C. Ecker
- TissueGnostics GmbH, 1020 Vienna, Austria;
- Translational Research Institute, 37 Kent Street, Woolloongabba, QLD 4102, Australia; (A.F.); (J.B.)
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia
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