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1
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Li JJ, Mao JX, Zhong HX, Zhao YY, Teng F, Lu XY, Zhu LY, Gao Y, Fu H, Guo WY. Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review. World J Hepatol 2024; 16:537-549. [PMID: 38689749 PMCID: PMC11056903 DOI: 10.4254/wjh.v16.i4.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/11/2024] [Accepted: 03/18/2024] [Indexed: 04/24/2024] Open
Abstract
The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
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Affiliation(s)
- Jing-Jing Li
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Jia-Xi Mao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Han-Xiang Zhong
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yuan-Yu Zhao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Fei Teng
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Xin-Yi Lu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Li-Ye Zhu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Yang Gao
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Hong Fu
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Wen-Yuan Guo
- Department of Liver Surgery and Organ Transplantation, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
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2
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Fattahi F, Saeednejad Zanjani L, Vafaei S, Habibi Shams Z, Kiani J, Naseri M, Gheytanchi E, Madjd Z. Expressions of TWIST1 and CD105 markers in colorectal cancer patients and their association with metastatic potential and prognosis. Diagn Pathol 2021; 16:26. [PMID: 33752711 PMCID: PMC7983220 DOI: 10.1186/s13000-021-01088-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 03/10/2021] [Indexed: 01/06/2023] Open
Abstract
Background TWIST1 and CD105, which contribute to tumor malignancy, are overexpressed in cancers. Accordingly, TWIST1 enhances epithelial-to-mesenchymal transition (EMT) and promotes the formation of cancer stem cells (CSCs). Also, CD105 is a neoangiogenesis marker in endothelial cells, which is introduced as a CSC marker in tumoral epithelial cells in several types of cancers. The present study was aimed to investigate expressions of TWIST1 and CD105 in colorectal cancer (CRC) patients. Methods Expressions of TWIST1 and CD105 in 250 CRC tissue samples were evaluated using immunohistochemistry on tissue microarrays (TMAs). In this regard, TWIST1 expression was investigated in the subcellular locations (cytoplasm and nucleus), while CD105 was mapped in endothelial cells and cytoplasmic tumor cells of CRC tissues. The association between the expression of these markers and clinicopathological parameters, as well as survival outcomes were analyzed. Results Results indicate a statistically significant association between higher nuclear expression levels of TWIST1 and distant metastases in CRC (P = 0.040) patients. In addition, it was shown that the increased nuclear expression of TWIST1 had a poor prognostic value for disease-specific survival (DSS) and progression-free survival (PFS) (P = 0.042, P = 0.043, respectively) in patients with CRC. Moreover, analysis of CD105 expression level has revealed that there is a statistically significant association between the increased expression of CD105 in tumoral epithelial cells and more advanced TNM stage (P = 0.050). Conclusions Our results demonstrate that nuclear TWIST1 and cytoplasmic CD105 expressions in tumor cells had associations with more aggressive tumor behavior and more advanced diseases in CRC cases.
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Affiliation(s)
- Fahimeh Fattahi
- Oncopathology Research Center, Iran University of Medical Sciences , Postal Code: 14496-14530, Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran.,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Leili Saeednejad Zanjani
- Oncopathology Research Center, Iran University of Medical Sciences , Postal Code: 14496-14530, Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran
| | - Somayeh Vafaei
- Oncopathology Research Center, Iran University of Medical Sciences , Postal Code: 14496-14530, Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran.,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Jafar Kiani
- Oncopathology Research Center, Iran University of Medical Sciences , Postal Code: 14496-14530, Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran.,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marzieh Naseri
- Oncopathology Research Center, Iran University of Medical Sciences , Postal Code: 14496-14530, Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran.,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elmira Gheytanchi
- Oncopathology Research Center, Iran University of Medical Sciences , Postal Code: 14496-14530, Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran
| | - Zahra Madjd
- Oncopathology Research Center, Iran University of Medical Sciences , Postal Code: 14496-14530, Hemmat Street (Highway), Next to Milad Tower, Tehran, Iran. .,Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Department of Pathology, Iran University of Medical Sciences, Tehran, Iran.
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Sun P, Shi A, Shen C, Liu Y, Wu G, Feng J. Human salivary histatin-1 (Hst1) promotes bone morphogenetic protein 2 (BMP2)-induced osteogenesis and angiogenesis. FEBS Open Bio 2020; 10:1503-1515. [PMID: 32484586 PMCID: PMC7396425 DOI: 10.1002/2211-5463.12906] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/25/2020] [Accepted: 05/28/2020] [Indexed: 12/26/2022] Open
Abstract
Large‐volume bone defects can result from congenital malformation, trauma, infection, inflammation and cancer. At present, it remains challenging to treat these bone defects with clinically available interventions. Allografts, xenografts and most synthetic materials have no intrinsic osteoinductivity, and so an alternative approach is to functionalize the biomaterial with osteoinductive agents, such as bone morphogenetic protein 2 (BMP2). Because it has been previously demonstrated that human salivary histatin‐1 (Hst1) promotes endothelial cell adhesion, migration and angiogenesis, we examine here whether Hst1 can promote BMP2‐induced bone regeneration. Rats were given subcutaneous implants of absorbable collagen sponge membranes seeded with 0, 50, 200 or 500 μg Hst1 per sample and 0 or 2 μg BMP2 per sample. At 18 days postsurgery, rats were sacrificed, and implanted regional tissue was removed for micro computed tomography (microCT) analyses of new bone (bone volume, trabecular number and trabecular separation). Four samples per group were decalcified and subjected to immunohistochemical staining to analyze osteogenic and angiogenic markers. We observed that Hst1 increased BMP2‐induced new bone formation in a dose‐dependent manner. Co‐administration of 500 μg Hst1 and BMP2 resulted in the highest observed bone volume and trabecular number, the lowest trabecular separation and the highest expression of osteogenic markers and angiogenic markers. Our results suggest that coadministration of Hst1 may enhance BMP2‐induced osteogenesis and angiogenesis, and thus may have potential for development into a treatment for large‐volume bone defects.
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Affiliation(s)
- Ping Sun
- The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, Hangzhou, China
| | - Andi Shi
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam (VU), Amsterdam Movement Science (AMS), Amsterdam, the Netherlands.,Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam (VU), Amsterdam Movement Sciences (AMS), Amsterdam, the Netherlands.,Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Chenxi Shen
- Laboratory for Myology, Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam (VU), Amsterdam Movement Sciences (AMS), Amsterdam, the Netherlands
| | - Yi Liu
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Gang Wu
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam (VU), Amsterdam Movement Science (AMS), Amsterdam, the Netherlands.,Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU), Amsterdam, the Netherlands
| | - Jianying Feng
- School of Dentistry, Zhejiang Chinese Medical University, Hangzhou, China
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Kiang KMY, Zhang P, Li N, Zhu Z, Jin L, Leung GKK. Loss of cytoskeleton protein ADD3 promotes tumor growth and angiogenesis in glioblastoma multiforme. Cancer Lett 2020; 474:118-126. [PMID: 31958485 DOI: 10.1016/j.canlet.2020.01.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 12/20/2022]
Abstract
Adducin 3 (ADD3) is a crucial assembly factor in the actin cytoskeleton and has been found to be aberrantly expressed in various cancers, including glioblastoma multiforme (GBM). It has previously been studied in array-based studies with controversial findings as to its functional role in glioma. In microarray analyses of 452 glioma specimens, we found significant downregulation of ADD3 in GBM, but not in less malignant gliomas, compared to normal brain tissue, which suggests that its downregulation might underlie critical events during malignant progression. We also found that ADD3 was functionally dependent on cell-matrix interaction. In our in vivo study, the proliferative and angiogenic capacity of ADD3-depleted GBM cells was promoted, possibly through PCNA, while p53 and p21 expression was suppressed, and pro-angiogenic signals were induced through VEGF-VEGFR-2-mediated activation in endothelial cells. With correlative in vitro, in vivo, and clinical data, we provide compelling evidence on the putative tumor-suppressive role of ADD3 in modulating GBM growth and angiogenesis. As a preclinical study, our research offers a better understanding of the pathogenesis of glioma malignant progression for the benefit of future investigations.
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Affiliation(s)
- Karrie Mei-Yee Kiang
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Pingde Zhang
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Ning Li
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Zhiyuan Zhu
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Lei Jin
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Gilberto Ka-Kit Leung
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
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Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis. J Virol 2017; 91:JVI.01235-17. [PMID: 28794048 DOI: 10.1128/jvi.01235-17] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 08/06/2017] [Indexed: 12/11/2022] Open
Abstract
Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from in vitro analysis suggested that the antiapoptosis Bcl2 protein, proliferation-related cyclin D1 protein, and CSC-associated Hes1, Notch1, Nanog, and Sox2 proteins are enhanced during infection or ectopic expression of HCV core protein.IMPORTANCE Endoglin plays a crucial role in fibrogenesis and angiogenesis and is an important protein for tumor growth, survival, and cancer cell metastasis. Endoglin enhances ALK1-SMAD1/5 signaling in different cell types, leading to increased proliferation and migration responses. We have observed endoglin expression on the HCV core-expressing cell surface of human hepatocyte origin and activation of phospho-SMAD1/5 and ID1 downstream signaling molecules. ID1 protein plays a role in CSC properties, and we found that this pathway is important for antiapoptotic and cell proliferation signaling. Blocking of endoglin-ALK1-SMAD1/5 might be a good candidate for therapy for liver cancer stem cells together with liver cirrhosis.
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Opławski M, Michalski M, Witek A, Michalski B, Zmarzły N, Jęda-Golonka A, Styblińska M, Gola J, Kasprzyk-Żyszczyńska M, Mazurek U, Plewka A. Identification of a gene expression profile associated with the regulation of angiogenesis in endometrial cancer. Mol Med Rep 2017; 16:2547-2555. [PMID: 28656251 PMCID: PMC5547990 DOI: 10.3892/mmr.2017.6868] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 02/20/2017] [Indexed: 12/11/2022] Open
Abstract
The publication of the human genome sequence provided direction in the search for novel diagnostic and therapeutic methods for the treatment of human diseases. The aim of the present study was to investigate the hypothesis that the expression profile of genes involved in the regulation of angiogenesis may be a marker in endometrial cancer that facilitates the diagnosis and prognosis of patients, as well as the identification of novel therapeutic targets. The current study included 36 patients with grade (G) 1 to 3 endometrial cancer, and a control group of patients consisting of females that qualified for the removal of the uterus. Out of these, 28 samples (control, 3; G1, 7; G2, 12; and G3, 6) were selected for microarray analysis. Molecular analysis of the endometrial samples involved the extraction of total RNA, purification of the obtained extracts and subsequent analysis of the gene expression profiles using an oligonucleotide microarray technique (GeneChip® Human Genome U133A plates). The results indicated that the mRNA expression profile of genes involved in the regulation of angiogenesis varies depending on the degree of histological differentiation of endometrial adenocarcinoma. Similar results were obtained from descriptive statistics characterizing the expression profile of 691 mRNAs associated with the regulation of angiogenesis in the groups of patients with endometrial adenocarcinoma. In addition, the results of the present study indicated that neuropilin2 (NRP2) may serve an important role in the activity of endothelial cells, and may affect vascular endothelial growth factor, and potentially plexins and integrins via regulation of their functions. An understanding of how these proteins interact remains to be determined; however, elucidating these interactions may provide an explanation for the mechanisms underlying angiogenesis. In conclusion, the results of the present study suggest that NRP2 may be a valuable target for investigation in future pharmacological studies involving angiogenesis in endometrial cancer.
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Affiliation(s)
- Marcin Opławski
- Department of Proteomics, School of Pharmacy, Division of Medical Analytics, Medical University of Silesia, Sosnowiec 41‑200, Poland
| | - Mateusz Michalski
- Department of Gynecological Oncology, Gynecology and Obstetrics, Regional Railway Hospital, Katowice 40‑760, Poland
| | - Andrzej Witek
- Department of Gynecology, Obstetrics and Oncologic Gynecology, Medical University of Silesia, Katowice 40‑752, Poland
| | - Bogdan Michalski
- Department of Oncological Gynaecology, School of Health Sciences, Medical University of Silesia, Katowice 40‑752, Poland
| | - Nikola Zmarzły
- Department of Molecular Biology, School of Pharmacy, Division of Medical Analytics, Medical University of Silesia, Sosnowiec 41‑200, Poland
| | - Agnieszka Jęda-Golonka
- Department of Gynecological Oncology, Gynecology and Obstetrics, Regional Railway Hospital, Katowice 40‑760, Poland
| | - Maria Styblińska
- Department of Molecular Biology, School of Pharmacy, Division of Medical Analytics, Medical University of Silesia, Sosnowiec 41‑200, Poland
| | - Joanna Gola
- Department of Molecular Biology, School of Pharmacy, Division of Medical Analytics, Medical University of Silesia, Sosnowiec 41‑200, Poland
| | - Małgorzata Kasprzyk-Żyszczyńska
- Department of Proteomics, School of Pharmacy, Division of Medical Analytics, Medical University of Silesia, Sosnowiec 41‑200, Poland
| | - Urszula Mazurek
- Department of Molecular Biology, School of Pharmacy, Division of Medical Analytics, Medical University of Silesia, Sosnowiec 41‑200, Poland
| | - Andrzej Plewka
- Department of Proteomics, School of Pharmacy, Division of Medical Analytics, Medical University of Silesia, Sosnowiec 41‑200, Poland
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Cho T, Shiozawa E, Urushibara F, Arai N, Funaki T, Takehara Y, Tazawa S, Misawa M, Homma M, Norose T, Omatsu M, Miyachi H, Yamochi T, Kunimura T, Tate G, Ishida F, Kudo SE, Takimoto M. The role of microvessel density, lymph node metastasis, and tumor size as prognostic factors of distant metastasis in colorectal cancer. Oncol Lett 2017; 13:4327-4333. [PMID: 28599434 DOI: 10.3892/ol.2017.5959] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 03/07/2017] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis is essential for tumor growth and metastasis. CD105 is reportedly a specific marker for tumor angiogenesis. It has been demonstrated that monoclonal antibodies to CD105 have high affinity for activated endothelial cells. A relationship between metastasis and microvessel density (MVD), as an indicator of neovascularization, has been identified in patients with colorectal cancer as shown by the presence of monoclonal antibodies to CD105. However, data on potentially confounding factors such as lymphatic and vascular infiltration and tumor size are lacking. We further investigated the relationship between MVD and distant metastasis, along with potentially confounding clinicopathological factors, to more precisely characterize this relationship. In this retrospective study, we analyzed colorectal cancer specimens surgically or endoscopically resected from January to September 2009. We defined MVD as the number of microvessels stained by monoclonal antibodies to CD105 per ×400 field. Selected clinicopathological factors were analyzed and stepwise multivariate logistic regression was performed to identify independent risk factors for distant metastasis. We analyzed 129 lesions. The median follow-up time was 34 months (range, 6-85 months) in patients with distant metastasis and 61 months (range, 60-86 months) in those without distant metastasis. At the time of resection or during subsequent follow-up, 32 patients had distant metastases. The MVD was significantly greater in patients with than without distant metastases (mean ± standard deviation: 10.4±4.9 vs. 7.6±3.3, P=0.008; Welch's t-test). Stepwise multivariate logistic regression indicated that MVD, regional lymph node metastasis, and tumor size were independent risk factors for distant metastases. Combining assessment of monoclonal antibodies to CD105-positive MVD with assessment of regional lymph node metastasis and tumor size may help to identify patients who need more intensive surveillance after surgery for colorectal cancer.
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Affiliation(s)
- Tomonari Cho
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Eisuke Shiozawa
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Fumihiko Urushibara
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Nana Arai
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Toshitaka Funaki
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Yusuke Takehara
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Sakiko Tazawa
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Masashi Misawa
- Digestive Disease Center, Showa University Northern Yokohama Hospital, Tsuzuki-ku, Yokohama 224-8503, Japan
| | - Mayumi Homma
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Tomoko Norose
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Mutsuko Omatsu
- Department of Clinico-Diagnostic Pathology, Showa University Northern Yokohama Hospital, Tsuzuki-ku, Yokohama 224-8503, Japan
| | - Hideyuki Miyachi
- Digestive Disease Center, Showa University Northern Yokohama Hospital, Tsuzuki-ku, Yokohama 224-8503, Japan
| | - Toshiko Yamochi
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Toshiaki Kunimura
- Department of Clinico-Diagnostic Pathology, Showa University Northern Yokohama Hospital, Tsuzuki-ku, Yokohama 224-8503, Japan
| | - Genshu Tate
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Fumio Ishida
- Digestive Disease Center, Showa University Northern Yokohama Hospital, Tsuzuki-ku, Yokohama 224-8503, Japan
| | - Shin-Ei Kudo
- Digestive Disease Center, Showa University Northern Yokohama Hospital, Tsuzuki-ku, Yokohama 224-8503, Japan
| | - Masahumi Takimoto
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan
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de Souza LB, de Oliveira LC, Nonaka CFW, Lopes MLDDS, Pinto LP, Queiroz LMG. Immunoexpression of GLUT-1 and angiogenic index in pleomorphic adenomas, adenoid cystic carcinomas, and mucoepidermoid carcinomas of the salivary glands. Eur Arch Otorhinolaryngol 2017; 274:2549-2556. [PMID: 28299426 DOI: 10.1007/s00405-017-4530-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Accepted: 03/07/2017] [Indexed: 12/21/2022]
Abstract
This study aimed to evaluate and compare the immunoexpression of glucose transporter-1 (GLUT-1) and angiogenic index between pleomorphic adenomas (PAs), adenoid cystic carcinomas (ACCs), and mucoepidermoid carcinomas (MECs) of the salivary glands, and establish associations with the respective subtype/histological grade. Twenty PAs, 20 ACCs, and 10 MECs were submitted to morphological and immunohistochemical analysis. GLUT-1 expression was semi-quantitatively evaluated and angiogenic index was assessed by microvessel counts using anti-CD34 antibody. Higher GLUT-1 immunoexpression was observed in the MECs compared to PAs and ACCs (p = 0.022). Mean number of microvessels was 66.5 in MECs, 40.4 in PAs, and 21.2 in ACCs (p < 0.001). GLUT-1 expression and angiogenic index showed no significant correlation in the tumors studied. Results suggest that differences in biological behavior of the studied tumors are related to GLUT-1. Benign and malignant salivary gland tumors differ in the angiogenic index; however, angiogenesis may be independent of the tumor cell's metabolic demand.
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Affiliation(s)
- Lélia Batista de Souza
- Postgraduate Program in Oral Pathology, Federal University of Rio Grande do Norte, Natal, RN, Brazil. .,Departamento de Odontologia, Universidade Federal do Rio Grande do Norte, Av. Senador Salgado Filho, 1787, Lagoa Nova, Natal, RN, CEP 59056-000, Brazil.
| | - Lucileide Castro de Oliveira
- Postgraduate Program in Oral Pathology, Federal University of Rio Grande do Norte, Natal, RN, Brazil.,Department of Pathology and Forensic Medicine, Federal University of Amazonas, Manaus, AM, Brazil
| | | | | | - Leão Pereira Pinto
- Postgraduate Program in Oral Pathology, Federal University of Rio Grande do Norte, Natal, RN, Brazil
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Martinović Ž, Kovač D, Martinović C. Recurrences in stage II rectal carcinoma after curative resection alone: from the viewpoint of angiogenesis. World J Surg Oncol 2016; 14:122. [PMID: 27102733 PMCID: PMC4840965 DOI: 10.1186/s12957-016-0877-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 04/15/2016] [Indexed: 12/12/2022] Open
Abstract
Background Angiogenesis plays a pivotal role in malignant tumor progression. The count of blood microvessels of the tumor has been recognized as an indicator of malignant potential of the tumors and provides the ability to predict tumors recurrence. The role endoglin in the Dukes B rectal cancer is still unexplored. The aims of this study were to examine immunohistochemical expression of endoglin in resected rectal cancer and investigate the relationship of tumor recurrence and other clinicopathological variables to the endoglin-assessed microvessel density of the tumor tissue and distal resection margins. Methods The study included 95 primary rectal adenocarcinomas, corresponding to 95 distal and 95 proximal resection margin specimens from surgical resection samples. Tumor specimens were paraffin embedded, and immunohistochemical staining for the CD105 endothelial antigen was performed to count CD105-MVD. For exact measurement of the CD105-MVD used, a computer-integrated system Alphelys Spot Browser 2 was used. Results The MVD was significantly higher in the tumor samples compared with the distal resection margins (p < 0.0001) and the proximal resection margins (p < 0.0001). There was no significant difference in the MVD between distal and proximal resection margins (p = 0.147). The type of surgical resection was a significant factor for determining the recurrence of tumors (p = 0.0104). There was no significant effect of patients’ age, gender, tumor location, grade of differentiation, histological tumor type, and the size and depth of tumor invasion on the recurrence of the tumor. The recurrence rate was significantly higher in the low CD105-MVD group of patients than in the high CD105-MVD group of patients (log rank test, p = 0.0406). Result of the multivariate analysis showed that the type of surgery (p = 0.0086), MVD tumors (p = 0.0385), and MVD of proximal resection margin (p = 0.0218) were the independent prognostic factors for the recurrent tumors. Conclusions CD105-assessed MVD could help to identify patients with more aggressive disease and increased risk of developing tumor recurrence after surgical treatment in stage II rectal cancer (RC).
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Affiliation(s)
- Željko Martinović
- Department of Surgery, Croatian Hospital "Dr. Fra Mato Nikolić", 72 276, Nova Bila, Bosnia and Herzegovina.
| | - Dražen Kovač
- Department of Pathology, School of Medicine, University of Rijeka, 51 000, Rijeka, Croatia
| | - Cvita Martinović
- Department of Internal Medicine, Croatian Hospital "Dr. Fra Mato Nikolić", 72 276, Nova Bila, Bosnia and Herzegovina
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Karmani L, Levêque P, Bouzin C, Bol A, Dieu M, Walrand S, Vander Borght T, Feron O, Grégoire V, Bonifazi D, Michiels C, Lucas S, Gallez B. Biodistribution of (125)I-labeled anti-endoglin antibody using SPECT/CT imaging: Impact of in vivo deiodination on tumor accumulation in mice. Nucl Med Biol 2016; 43:415-23. [PMID: 27179250 DOI: 10.1016/j.nucmedbio.2016.03.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 03/25/2016] [Accepted: 03/26/2016] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Radiolabeled antibodies directed against endoglin (CD105) are promising tools for imaging and antiangiogenic cancer therapy. To validate iodinated antibodies as reliable tracers, we investigated the influence of the radiolabeling method (direct or indirect) on their in vivo stability. METHODS Anti-CD105 mAbs were radioiodinated directly using chloramine-T ((125)I-anti-CD105-mAbs) or indirectly using D-KRYRR peptide as a linker ((125)I-KRYRR-anti-CD105-mAbs). The biodistribution was studied in B16 tumor-bearing mice via SPECT/CT imaging. RESULTS Radioiodinated mAbs were stable in vitro. In vivo, thyroid showed the most important increase of uptake after 24h for (125)I-anti-CD105-mAbs (91.9±4.0%ID/ml) versus(125)I-KRYRR-anti-CD105-mAbs (4.4±0.6%ID/ml). Tumor uptake of (125)I-anti-CD105-mAbs (0.9±0.3%ID/ml) was significantly lower than that of (125)I-KRYRR-anti-CD105-mAbs (4.7±0.2%ID/ml). CONCLUSIONS An accurate characterization of the in vivo stability of radioiodinated mAbs and the choice of an appropriate method for the radioiodination are required, especially for novel targets. The indirect radioiodination of internalizing anti-CD105 mAbs leads to more stable tracer by decreasing in vivo deiodination and improves the tumor retention of radioiodinated mAbs. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE To date, the only antiangiogenic antibody approved for clinical indications is bevacizumab. There is a need to develop more antibodies that have targets highly expressed on tumor endothelium. CD105 represents a promising marker of angiogenesis, but its therapeutic relevance in cancer needs to be further investigated. In this context, this study suggests the potential use of indirectly iodinated anti-CD105 mAbs for tumor imaging and for therapeutic purposes.
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Affiliation(s)
- Linda Karmani
- Biomedical Magnetic Resonance Research Group (REMA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, Avenue Mounier 73, 1200, Brussels, Belgium
| | - Philippe Levêque
- Biomedical Magnetic Resonance Research Group (REMA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, Avenue Mounier 73, 1200, Brussels, Belgium
| | - Caroline Bouzin
- Pharmacology and Therapeutics Unit (FATH), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Avenue Mounier 53, 1200, Brussels, Belgium
| | - Anne Bol
- Centre for Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Avenue Hippocrate 54, 1200, Brussels, Belgium
| | - Marc Dieu
- Unité de Recherche en Biologie Cellulaire (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium
| | - Stephan Walrand
- Centre for Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Avenue Hippocrate 54, 1200, Brussels, Belgium
| | - Thierry Vander Borght
- Centre for Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Avenue Hippocrate 54, 1200, Brussels, Belgium
| | - Olivier Feron
- Pharmacology and Therapeutics Unit (FATH), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Avenue Mounier 53, 1200, Brussels, Belgium
| | - Vincent Grégoire
- Centre for Molecular Imaging, Radiotherapy and Oncology (MIRO), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Avenue Hippocrate 54, 1200, Brussels, Belgium
| | - Davide Bonifazi
- Namur Research College and Department of Chemistry (NARC), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium
| | - Carine Michiels
- Unité de Recherche en Biologie Cellulaire (URBC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium
| | - Stéphane Lucas
- Research Centre for the Physics of Matter and Radiation (PMR), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles 61, 5000, Namur, Belgium
| | - Bernard Gallez
- Biomedical Magnetic Resonance Research Group (REMA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, Avenue Mounier 73, 1200, Brussels, Belgium.
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Autophagy and Neovascularization in Colorectal Cancer. CURRENT HEALTH SCIENCES JOURNAL 2015; 41:204-208. [PMID: 30534423 PMCID: PMC6246992 DOI: 10.12865/chsj.41.03.02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 01/29/2015] [Indexed: 11/18/2022]
Abstract
Purpose: This study aims to determinate the microvessel density at the base of the tumor, as well in tumor’s mass, in order to determinate the number of neovascularization vessels (marked with CD105) in comparison with presence or absence of autophagy puncta. Material/Methods: Standard immunohistochemistry was performed on 38 samples of colorectal adenocarcinoma, in order to determinate the presence of autophagy and neovascularization blood vessels with the help of LC3, CD34, CD31 and CD105 antibodies. Results: The autophagy process was observed in the cancerous cells and was noted as present in both regions of interest from the tumor. The mean number of blood vessels market with CD105 is higher in tumor mass then at its base, p value of the Student t test being highly significant (p<0.0001). Conclusions: The presence of autophagy puncta was notice in every case, both in the mass of the tumor and at its base. Microvascular density of new-grown blood vessels is higher in the mass of the tumor compared with the base of the tumor.
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Prognostic Significance of Microvessel Density Determining by Endoglin in Stage II Rectal Carcinoma: A Retrospective Analysis. Gastroenterol Res Pract 2015; 2015:504179. [PMID: 26089870 PMCID: PMC4454763 DOI: 10.1155/2015/504179] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 04/24/2015] [Accepted: 05/04/2015] [Indexed: 02/07/2023] Open
Abstract
Background. The role of endoglin in the Dukes B rectal cancer is still unexplored. The aim of this study was to examine the expression of endoglin (CD105) in resected rectal cancer and to evaluate the relationship between microvessels density (MVD), clinicopathological factors, and survival rates. Methods. The study included 95 primary rectal adenocarcinomas, corresponding to 67 adjacent and 73 distant normal mucosa specimens from surgical resection samples. Tumor specimens were paraffin-embedded and immunohistochemical staining for the CD105 endothelial antigen was performed to count CD105-MVD. For exact measurement of the CD105-MVD used a computer-integrated system Alphelys Spot Browser 2 was used. Results. The intratumoral CD105-MVD was significantly higher compared with corresponding adjacent mucosa (P < 0.0001) and distant mucosa specimens (P < 0.0001). There was no significant difference in the CD105-MVD according to patients age, gender, tumor location, grade of differentiation, histological type, depth of tumor invasion, and tumor size. The overall survival rate was significantly higher in the low CD105-MVD group of patients than in the high CD105-MVD group of patients (log-rank test, P = 0.0406). Conclusion. CD105-assessed MVD could help to identify patients with possibility of poor survival in the group of stage II RC.
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Evaluation of Angiogenesis in Colorectal Cancer. CURRENT HEALTH SCIENCES JOURNAL 2015; 41:145-151. [PMID: 30364821 PMCID: PMC6201204 DOI: 10.12865/chsj.41.02.09] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 04/01/2015] [Indexed: 11/18/2022]
Abstract
PURPOSE Angiogenesis is an important step in the process of cancer growth. The purpose of this study was to determine the neoangiogenesis with CD31, CD34 and CD105, and tried to observe the differences between these three antibodies. MATERIAL/METHODS The blood vessels stained with CD31, CD 34 and CD105 were counted, and we reported their number per square millimeter to obtain microvascular density (MVD). For angiogenesis quantification we determined the neoformation blood vessels with CD105. The CD31 and CD34 were used as control markers, in order to observe the difference between neoformation blood vessels and mature vessels. RESULTS Comparing the average effective vessels marked with the 3 markers, Student t test showed that the mean number of blood vessels market with CD 34 is higher than blood vessels market with CD31 and CD 105. The value of the Student t test was highly significant in all three cases (p<0.001). By calculating the Pearson correlation coefficient for the relationship CD31-CD105 we obtained a value r = 0.440, which corresponds to p = 0.0013 < 0.05, indicating a statistically significant direct correlation between the two factors. CONCLUSIONS An important number of vessels (around 40%) that can be found in tumor area are neoformation vessels, this concept being an important assessment for the choice of the correct and effective treatment in colorectal adenocarcinoma.
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Correlations Between Intratumoral Microvessel Density and Histopathological Type or Neoadjuvant Radiotherapy for Rectal Carcinoma. CURRENT HEALTH SCIENCES JOURNAL 2015; 41:152-157. [PMID: 30364876 PMCID: PMC6201205 DOI: 10.12865/chsj.41.02.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 04/01/2015] [Indexed: 11/25/2022]
Abstract
Purpose: This study aims to evaluate intratumoral microvessel density in rectal carcinoma cases with different histopathological type (adenocarcinoma and mucinous carcinoma) and different preoperatory neoadjuvant radiotherapy status (irradiated / non-irradiated) ,thus analyzing any possible statistical correlation between these parameters. Material and methods: Our prospective study consists in standard immunohistochemistry procedures using CD34, CD31 and CD105 antibodies, which were performed on 25 samples of rectal carcinoma, in order to determine intratumoral microvessel density. Results: The 25 case study group was divided either by histopathological type or by prior radiotherapeutical treatment as follows: 9 cases of mucinous carcinoma versus 16 cases of adenocarcinoma and 13 cases of rectal cancer that have not received neoadjuvant radiotherapy versus 12 cases of rectal cancer with preoperatory radiotherapy. Conclusions: The number of intratumoral microvessels is higher in non-irradiated rectal tumors and in adenocarcinomas, this remark being statistical significant (with only one exception – CD34 staining in non-irradiated versus irradiated tumors) for all types of vessels (new-grown and mature). This result is due to the benefic effect of neoadjuvant radiotherapy on decreasing angiogenic activity, thus having an important prognostic value for rectal cancer.
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Abstract
Endoglin is a homodimeric cell membrane glycoprotein receptor for transforming growth factor β and bone morphogenetic proteins. Endoglin is essential for angiogenesis, being densely expressed on proliferating endothelial cells and upregulated during hypoxia. Its expression is implicated in development of resistance to vascular endothelial growth factor (VEGF) inhibition. TRC105 is an antibody that binds endoglin and prevents endothelial cell activation. Targeting endoglin and the VEGF pathway concurrently improves treatment in vitro and appears to reverse resistance to bevacizumab in some refractory cancer patients. Randomized trials are under way to assess the clinical benefit of adding TRC105 therapy to bevacizumab therapy. Further trials are under way to assess the activity of TRC105 with small-molecule inhibitors of the VEGF pathway in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma. Stratification of soft tissue sarcomas based on endoglin expression levels is proposed to identify patients most likely to benefit from TRC105 treatment. The development of a TRC105 antibody-drug conjugate is also described.
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Affiliation(s)
- Lee S Rosen
- Hematology-Oncology, UCLA Medical Center Santa Monica, 2020 Santa Monica Blvd, Ste 600, Santa Monica, CA, 90404, USA,
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Sun H, Xu Y, Yang Q, Wang W. Assessment of tumor grade and angiogenesis in colorectal cancer: whole-volume perfusion CT. Acad Radiol 2014; 21:750-7. [PMID: 24809317 DOI: 10.1016/j.acra.2014.02.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Revised: 02/09/2014] [Accepted: 02/10/2014] [Indexed: 12/16/2022]
Abstract
RATIONALE AND OBJECTIVES The preoperative evaluation of tumor grading and angiogenesis has important clinical implications in the treatment and prognosis of patients with colorectal cancers (CRCs). The aim of the present study was to assess tumor perfusion with 256-slice computed tomography (CT) using whole-volume perfusion technology before surgery, and to investigate the differences in the perfusion parameters among tumor grades and the correlation between perfusion parameters and pathologic results in CRC. MATERIALS AND METHODS Thirty-seven patients with CRC confirmed by endoscopic pathology underwent whole-volume perfusion CT assessments with a 256-slice CT and surgery. Quantitative values for blood flow, blood volume, and time to peak were determined using commercial software. After surgery, resected specimens were analyzed immunohistochemically with CD105 antibodies for the quantification of microvessel density (MVD). The difference in CT perfusion parameters and MVD among different tumor differentiation grades was evaluated by the Student-Newman-Keuls test. The correlations between CT perfusion parameters and MVD were evaluated using the Pearson correlation analysis. RESULTS The mean blood flow was significantly different among well, moderately, and poorly differentiated groups (61.17 ± 17.97, 34.80 ± 13.06, and 22.24 ± 9.31 mL/minute/100 g, respectively; P < .05). The blood volume in the well-differentiated group was significantly higher than that in the moderately differentiated group (33.96 ± 24.81 vs. 16.93 ± 5.73 mL/100 g; P = .002) and that in the poorly differentiated group (33.96 ± 24.81 vs. 18.05 ± 6.01 mL/100 g; P = .009). The time to peak in the poorly differentiated group was significantly longer than that in the well-differentiated group (27.81 ± 11.95 vs. 17.60 ± 8.53 seconds; P = .016) and that in the moderately differentiated group (27.81 ± 11.95 vs. 18.94 ± 7.47 seconds; P = .028). There was no significant difference in the MVD among well, moderately, and poorly differentiated groups (33.47 ± 14.69, 28.89 ± 11.82, and 29.89 ± 11.02, respectively; P > .05). There was no significant correlation between CT perfusion parameters and MVD (r = 0.201, 0.295, and -0.178, respectively; P = .233, .076, and .292, respectively). CONCLUSIONS CT whole-volume perfusion technology has the potential to evaluate pathologic differentiation grade of CRC before surgery. However, preoperative perfusion CT parameters do not reflect the MVD of CRC.
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Can vascular endothelial growth factor and microvessel density be used as prognostic biomarkers for colorectal cancer? A systematic review and meta-analysis. ScientificWorldJournal 2014; 2014:102736. [PMID: 25143961 PMCID: PMC3985294 DOI: 10.1155/2014/102736] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 01/29/2014] [Indexed: 12/12/2022] Open
Abstract
Background. Vascular endothelial growth factor (VEGF) and microvessel density (MVD) are associated with greater incidence of metastases and decreased survival. Whether they can be used as prognostic indicators of colorectal cancer (CRC) is still controversial. Methods. The authors performed a meta-analysis using the results of a literature search of databases of PubMed and EMBASE, and the references of articles included in the analysis. Meta-analysis was performed using random effects model and hazard ratios (HRs) and 95% confidence intervals (CIs) as effect measures. Results. Twenty studies contributed to the analysis of VEGF, of which 16 were used for overall survival (OS) and 9 for disease-free survival (DFS). High VEGF levels has a relationship with unfavorable survival (OS: HR = 1.98, 95% CI: 1.30–3.02; DFS: HR = 2.10, 95% CI: 1.26–3.49) and a 4.22-fold increase in the rate of distant metastases. Analysis was performed on 18 studies for MVD; the results showed that patients with high MVD expression in tumors appeared to have poorer overall survival (HR = 1.39, 95% CI: 1.22–1.58) and were at a greater risk of having unfavorable clinical characteristics related to prognosis. Corresponding results were obtained from quantitative and/or qualitative analysis of clinicopathological. Conclusions. The meta-analysis demonstrates that VEGF and MVD can be used as prognostic biomarkers for CRC patients.
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Tobar N, Avalos MC, Méndez N, Smith PC, Bernabeu C, Quintanilla M, Martínez J. Soluble MMP-14 produced by bone marrow-derived stromal cells sheds epithelial endoglin modulating the migratory properties of human breast cancer cells. Carcinogenesis 2014; 35:1770-9. [PMID: 24618373 DOI: 10.1093/carcin/bgu061] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
It has been proposed that epithelial cells can acquire invasive properties through exposure to paracrine signals originated from mesenchymal cells within the tumor microenvironment. Transforming growth factor-β (TGF-β) has been revealed as an active factor that mediates the epithelial-stroma cross-talk that facilitates cell invasion and metastasis. TGF-β signaling is modulated by the coreceptor Endoglin (Eng), which shows a tumor suppressor activity in epithelial cells and regulates the ALK1-Smad1,5,8 as well as the ALK5-Smad2,3 signaling pathways. In the current work, we present evidence showing that cell surface Eng abundance in epithelial MCF-7 breast cancer cells is inversely related with cell motility. Shedding of Eng in MCF-7 cell surface by soluble matrix metalloproteinase-14 (MMP-14) derived from the HS-5 bone-marrow-derived cell line induces a motile epithelial phenotype. On the other hand, restoration of full-length Eng expression blocks the stromal stimulus on migration. Processing of surface Eng by stromal factors was demonstrated by biotin-neutravidin labeling of cell surface proteins and this processing generated a shift in TGF-β signaling through the activation of Smad2,3 pathway. Stromal MMP-14 abundance was stimulated by TGF-β secreted by MCF-7 cells acting in a paracrine manner. In turn, the stromal proteolytic activity of soluble MMP-14, by inducing Eng shedding, promoted malignant progression. From these data, and due to the capacity of TGF-β to regulate malignancy in epithelial cancer, we propose that stromal-dependent epithelial Eng shedding constitutes a putative mechanism that exerts an environmental control of cell malignancy.
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Affiliation(s)
- Nicolás Tobar
- Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain
| | - M Celeste Avalos
- Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain
| | - Nicolás Méndez
- Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain
| | - Patricio C Smith
- Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
| | - Carmelo Bernabeu
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and
| | - Miguel Quintanilla
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain
| | - Jorge Martínez
- Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain
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Karmani L, Bouchat V, Bouzin C, Levêque P, Labar D, Bol A, Deumer G, Marega R, Bonifazi D, Haufroid V, Michiels C, Grégoire V, Feron O, Lucas S, Vander Borght T, Gallez B. (89)Zr-labeled anti-endoglin antibody-targeted gold nanoparticles for imaging cancer: implications for future cancer therapy. Nanomedicine (Lond) 2014; 9:1923-37. [PMID: 24547782 DOI: 10.2217/nnm.13.185] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS Antibody-labeled gold nanoparticles represent an attractive tool for cancer imaging and therapy. In this study, the anti-CD105 antibody was conjugated with gold nanoparticles (AuNPs) for the first time. The antibody biodistribution in mice before and after conjugation to AuNPs was studied, with a focus on tumor targeting. MATERIALS & METHODS Antibodies were radiolabeled with 89Zr before conjugation to AuNPs (5 nm). Immunonanoconjugates were characterized in vitro in terms of size, stability in plasma and binding to the target. Quantitative PET imaging and ICP-MS analysis assessed in vivo distribution and specific tumor targeting of tracers. RESULTS The tumor uptake of immunoconjugates was preserved up to 24 h after injection, with high tumor contrast and selective tumor targeting. No major tracer accumulation was observed over time in nonspecific organs. ICP-MS analysis confirmed the antibody specificity after nanoparticle conjugation. CONCLUSION The anti-CD105 antibody conjugation to AuNPs did not greatly affect CD105-dependent tumor uptake and the efficacy of tumor targeting for cancer detection.
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Affiliation(s)
- Linda Karmani
- Biomedical Magnetic Resonance Group (REMA), Louvain Drug Research Institute, Université Catholique de Louvain, Avenue Mounier 73, 1200 Brussels, Belgium
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Ng L, Poon RTP, Pang R. Biomarkers for predicting future metastasis of human gastrointestinal tumors. Cell Mol Life Sci 2013; 70:3631-56. [PMID: 23370778 PMCID: PMC11113832 DOI: 10.1007/s00018-013-1266-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Revised: 01/02/2013] [Accepted: 01/10/2013] [Indexed: 12/19/2022]
Abstract
The recent advances in surgery and radiation therapy have significantly improved the prognosis of patients with primary cancer, and the major challenge of cancer treatment now is metastatic disease development. The 5-year survival rate of cancer patients who have distant metastasis at diagnosis is extremely low, suggesting that prediction and early detection of metastasis would definitely improve their prognosis because suitable patient therapeutic management and treatment strategy can be provided. Cancer cells from a primary site give rise to a metastatic tumor via a number of steps which require the involvement and altered expression of many regulators. These regulators may serve as biomarkers for predicting metastasis. Over the past few years, numerous regulators have been found correlating with metastasis. In this review, we summarize the findings of a number of potential biomarkers that are involved in cadherin-catenin interaction, integrin signaling, PI3K/Akt/mTOR signaling and cancer stem cell identification in gastrointestinal cancers. We will also discuss how certain biomarkers are associated with the tumor microenvironment that favors cancer metastasis.
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Affiliation(s)
- Lui Ng
- Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong SAR, China,
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Hansen TF, Nielsen BS, Jakobsen A, Sørensen FB. Visualising and quantifying angiogenesis in metastatic colorectal cancer : A comparison of methods and their predictive value for chemotherapy response. Cell Oncol (Dordr) 2013; 36:341-50. [PMID: 23838926 DOI: 10.1007/s13402-013-0139-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2013] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Angiogenesis plays an important role in tumour growth and dissemination. We have recently shown that blood vessel density, determined by image analysis based on microRNA-126 (miRNA-126) in situ hybridization (ISH) in the primary tumours of metastatic colorectal cancers (mCRC), is predictive of chemotherapy response. Here, we evaluated whether more general approaches to determine vessel density in primary tumours are equally predictive of chemotherapy response. METHODS This methodological study was carried out using paraffin embedded tissues from primary tumours of 89 patients with mCRC, who had all been treated with first-line chemotherapy (XELOX). Tissue sections from the deepest invasive tumour front were processed for miRNA-126 ISH and CD34 immunohistochemistry (IHC). Estimates of microvessel density (MVD) were obtained for both miRNA-126 and CD34 by quantitative image analyses (MVDi), vascular area per image (μm²) analyses, and manually counting vessels in vascular hot spots (MVDh). Clinical responses were evaluated according to Response Evaluation Criteria In Solid Tumours (RECIST). RESULTS The MVDi for miRNA-126 showed a significant correlation with treatment response (p=0.01), with a median value of 2,071 μm² (95% CI, 1,505-3,075 μm²) in the responder group compared to 1,337 μm² (95% CI, 1,038-1,499 μm²) in the non-responder group. This difference translated into a significant difference in progression free survival (p=0.01). CONCLUSIONS The methodological assessment of MVD and the molecular vessel marker are both important for the prediction of the chemotherapy response in mCRC. Our findings indicate that MVDi for miRNA-126 represents a powerful estimate and may serve as a clinical biomarker superior to MVDh.
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Muñoz R, Arias Y, Ferreras JM, Jiménez P, Langa C, Rojo MA, Gayoso MJ, Córdoba-Díaz D, Bernabéu C, Girbés T. In vitro and in vivo effects of an anti-mouse endoglin (CD105)-immunotoxin on the early stages of mouse B16MEL4A5 melanoma tumours. Cancer Immunol Immunother 2013; 62:541-51. [PMID: 23076642 PMCID: PMC11029560 DOI: 10.1007/s00262-012-1357-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Accepted: 09/25/2012] [Indexed: 10/27/2022]
Abstract
TGF-beta superfamily co-receptors are emerging as targets for cancer therapy, acting both directly on cells and indirectly on the tumour neovasculature. Endoglin (CD105), an accessory component of the TGF-beta receptor complex, is expressed in certain melanoma cell lines and the endothelial cells of tumour neovessels. Targeting endoglin with immunotoxins is an attractive approach for actively suppressing the blood supply to tumours. Here, we report evidence indicating that endoglin is expressed in mouse melanoma B16MEL4A5 and mouse fibroblast L929 cell lines. We prepared an immunotoxin to target endoglin by coupling the rat anti-mouse MJ7/18 (IgG2a) monoclonal antibody (mAb) to the non-toxic type 2 ribosome-inactivating protein nigrin b (Ngb) with N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) as a linker with a molar nigrin b at a MJ7/18 stoichiometry of 2:1. The MJ7-Ngb immunotoxin generated killed both cell lines, with IC50 values of 4.2 × 10(-9) M for B16MEL4A5 and 7.7 × 10(-11) M for L929 cells. For in vivo assays of the immunotoxin, B16MEL4A5 cells were injected subcutaneously into the right flanks of 6-week-old C57BL/6 J mice. When the animals developed palpable solid tumours, they were subjected to treatment with the immunotoxin. While treatment with either MJ7/18 mAb or Ngb did not affect tumour development, treatment with the immunotoxin completely and steadily blocked tumour growth up to 7 days, after which some tumours re-grew. Thus, vascular-targeting therapy with this anti-vascular immunotoxin could promote the destruction of newly created tumour vessels at early stages of B16MEL4A5 tumour development and readily accessible CD105+ B16MEL4A5 melanoma cells.
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Affiliation(s)
- Raquel Muñoz
- Facultad de Ciencias, Departamento de Bioquímica y Biología Molecular, Universidad de Valladolid, 47005 Valladolid, Spain
| | - Yolanda Arias
- Facultad de Ciencias, Departamento de Bioquímica y Biología Molecular, Universidad de Valladolid, 47005 Valladolid, Spain
| | - José Miguel Ferreras
- Facultad de Ciencias, Departamento de Bioquímica y Biología Molecular, Universidad de Valladolid, 47005 Valladolid, Spain
| | - Pilar Jiménez
- Nutrición y Bromatología-Facultad de Medicina y Centro de Investigación en Nutrición, Alimentación y Dietética (CINAD), Universidad de Valladolid, 47005 Valladolid, Spain
| | - Carmen Langa
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain
| | - María Angeles Rojo
- Escuela Politécnica, Universidad Europea Miguel de Cervantes, 47012 Valladolid, Spain
| | - Manuel José Gayoso
- Facultad de Medicina, Departamento de Biología Celular, Histología y Farmacología, Universidad de Valladolid, 47005 Valladolid, Spain
| | - Damián Córdoba-Díaz
- Facultad de Farmacia, Departamento de Farmacia y Tecnología Farmacéutica, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Carmelo Bernabéu
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain
| | - Tomás Girbés
- Nutrición y Bromatología-Facultad de Medicina y Centro de Investigación en Nutrición, Alimentación y Dietética (CINAD), Universidad de Valladolid, 47005 Valladolid, Spain
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Kim SK, Romero R, Savasan ZA, Xu Y, Dong Z, Lee DC, Yeo L, Hassan SS, Chaiworapongsa T. Endoglin in amniotic fluid as a risk factor for the subsequent development of bronchopulmonary dysplasia. Am J Reprod Immunol 2012; 69:105-23. [PMID: 23279628 DOI: 10.1111/aji.12046] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 10/23/2012] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Cross-talk between inflammation and angiogenesis pathways has been recently reported. The objectives of this study were to: (i) examine whether amniotic fluid (AF) concentrations of soluble endoglin (sEng), a protein with anti-angiogenic properties, change during pregnancy, parturition, or intra-amniotic infection and/or inflammation (IAI); (ii) determine whether an increase in sEng in the AF of patients with preterm labor (PTL) and preterm prelabor rupture of membranes (PROM) is associated with adverse neonatal outcomes; and (iii) investigate potential sources of sEng in AF. STUDY DESIGN A cross-sectional study was conducted to include patients in the following groups: (i) mid-trimester (n = 20); (ii) PTL with term delivery (n = 95); (iii) PTL leading to preterm delivery with (n = 40) and without IAI (n = 46); (iv) preterm PROM with (n = 37) and without IAI (n = 37); (v) term in labor (n = 48) and not in labor (n = 44). AF concentrations of sEng were determined by enzyme-linked immunosorbent assay. Chorioamniotic membranes, umbilical cord blood, and AF macrophages were examined for the expression of endoglin. RESULTS (i) Patients with IAI had a higher median AF concentration of sEng than those without IAI (P = 0.02 for PTL and 0.06 for preterm PROM); (ii) AF concentrations of sEng in the 3rd and 4th quartiles were associated with IAI (OR 2.5 and 7.9, respectively); (iii) an AF sEng concentration ≥779.5 pg/mL was associated with bronchopulmonary dysplasia (BPD) (OR 7.9); (iv) endoglin was co-localized with CD14+ macrophages in AF pellets of patients with IAI by immunofluorescence and flow cytometry; and (v) the concentration of sEng in the supernatant was significantly increased after the treatment of macrophages with endotoxin or TNF-α. CONCLUSIONS Soluble endoglin participates in the host response against IAI. Activated macrophages may be a source of sEng concentrations in the AF of patients with IAI. An increase of sEng in the AF is associated with BPD and adverse neonatal outcomes.
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Affiliation(s)
- Sun K Kim
- Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD and Detroit, MI 48201, USA
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Gurzu S, Cimpean AM, Kovacs J, Jung I. Counting of angiogenesis in colorectal carcinomas using double immunostain. TUMORI JOURNAL 2012; 98:485-490. [PMID: 23052166 DOI: 10.1177/030089161209800414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The aim of the study was to compare the simple immunostains performed with CD31, CD34 and CD105 antibodies, with double-labeling immunostains realized with CD105 (endoglin) and smooth muscle actin antibodies in colorectal carcinomas. Fourty colorectal carcinoma surgical specimens were immunohistochemically studied. Quantification of microvessel density was realized at 400× magnification, in the intratumoral and peritumoral areas and distant from the tumor. With simple immunostains, it was very difficult to identify the type of vessel. With CD105/smooth muscle actin double-labeling stain we determined vessels maturation grade and identified the following types of vessels: isolated endothelial cells, immature, intermediary, mature and activated mature vessels. The density of intermediate vessels was higher in well-differentiated (2 ± 0.03) than in moderately (0.14 ± 0,02) or poorly differentiated colorectal carcinoma (0.07 ± 0.01). Such vessel types could not be identified with simple immunostains, and we believe that this is one reason why double-labeling immunostaining with CD105/smooth muscle actin should be used to study angiogenesis in colorectal carcinoma. We conclude that the density of intermediate vessels, correlated with the histological grade, could indicate the success or failure of the antiangiogenic treatment. Double-labeling immunostaining is indispensable to study vessel maturation grade.
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Affiliation(s)
- Simona Gurzu
- Department of Pathology, University of Medicine and Pharmacy of Targu Mures, Romania
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Targeting the tumor microenvironment: focus on angiogenesis. JOURNAL OF ONCOLOGY 2011; 2012:281261. [PMID: 21876693 PMCID: PMC3163131 DOI: 10.1155/2012/281261] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/01/2011] [Accepted: 06/23/2011] [Indexed: 02/07/2023]
Abstract
Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.
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Martins SF, Reis RM, Rodrigues AM, Baltazar F, Filho AL. Role of endoglin and VEGF family expression in colorectal cancer prognosis and anti-angiogenic therapies. World J Clin Oncol 2011; 2:272-80. [PMID: 21773077 PMCID: PMC3139037 DOI: 10.5306/wjco.v2.i6.272] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 03/02/2011] [Accepted: 04/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the cancer models and most of the carcinogenic steps are presently well understood. Therefore, successful preventive measures are currently used in medical practice. However, CRC is still an important public health problem as it is the third most common cancer and the fourth most frequent cause of cancer death worldwide. Nowadays, pathologic stage is a unique and well-recognized prognostic indicator, however, more accurate indicators of the biologic behavior of CRC are expected to improve the specificity of medical treatment. Angiogenesis plays an important role in the growth and progression of cancer but its role as a prognostic factor is still controversial. Probably the most important clinical implication of tumor angiogenesis is the development of anti-angiogenic therapy. The goal of this review is to critically evaluate the role of angiogenic markers, assessed by either endoglin-related microvessel density or expression of vascular endothelial growth factor family members in the CRC setting and discuss the role of these angiogenic markers in anti-angiogenic therapies.
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Affiliation(s)
- Sandra F Martins
- Sandra F Martins, Rui M Reis, Fátima Baltazar, Adhemar Longatto Filho, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Portugal - Campos of Gualtar - 4710-057 Braga, Portugal
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Kuiper P, Hawinkels LJAC, Jonge-Muller ESMD, Biemond I, Lamers CBHW, Verspaget HW. Angiogenic markers endoglin and vascular endothelial growth factor in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol 2011; 17:219-25. [PMID: 21245995 PMCID: PMC3020376 DOI: 10.3748/wjg.v17.i2.219] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Revised: 09/09/2010] [Accepted: 09/16/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression and potential prognostic role of vascular endothelial growth factor (VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
METHODS: Microvessel density (MVD) in GEP-NETs was evaluated using endoglin and CD31 immunohistochemistry. In addition, tissue levels of endoglin and VEGF were determined in homogenates by ELISA.
RESULTS: Endoglin was highly expressed on tumor endothelial cells. CD31 MVD in GEP-NETs was significantly higher compared to endoglin MVD (P < 0.01). Two- to four-fold higher tissue levels of endoglin and VEGF were seen in tumors compared to associated normal tissue. This increased endoglin tissue expression in tumors was significantly related to tumor size (P < 0.01), presence of metastases (P = 0.04), and a more advanced tumor stage (P = 0.02), whereas expression of VEGF was not.
CONCLUSION: We suggest that endoglin is a potential marker to indicate and predict metastases, which might be useful in the post-resection therapeutic approach of patients with GEP-NETs.
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Immunohistochemical analysis of vascular density and area in colorectal carcinoma using different markers and comparison with clinicopathologic prognostic factors. Tumour Biol 2011; 32:527-34. [PMID: 21222066 DOI: 10.1007/s13277-010-0147-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Accepted: 12/10/2010] [Indexed: 12/22/2022] Open
Abstract
Analysis of blood and lymphatic vessel in colorectal cancer is controversial in the literature, possibly due to variations in the methods of analysis. In this study, it was aimed to search for a reliable approach in the quantification of angio- and lymphangiovascular density and area as a prognostic factor and to compare such vessel counts in normal mucosa, adenomas and cancer. A retrospective study was performed on 60 sporadic colorectal cancer, 30 colorectal adenomas, and 10 colorectal non-neoplastic lesions. Archival tissues were submitted to immunohistochemical evaluation using antibodies to CD31, CD34, CD105, VEGF-A, VEGF-C, and D2-40. Microvessel density and total vascular area were determined by computer image analysis and values were compared in the three groups of lesions; the prognostic value of these parameters was evaluated in the group of colorectal cancer. Most markers showed progressive vessel counts from non-neoplastic tissue to carcinoma, both for microvessel density and total vascular area. Only microvessel density determined by CD34 in the central areas of the cancer correlated with recurrence/metastasis (p = 0.04) and survival (p = 0.02). Different methods of quantification (microvessel counting versus estimation of total vascular area), immunohistochemical markers (pan-endothelial marker versus neovessels and lymphatic markers), and areas of analysis (periphery versus inner portions of the lesion) were assessed using image analysis. The results corroborate the increase in vascularization of carcinoma and suggest that microvessel density determined by immunostaining for CD34 in the inner portion of the tumor might represent a prognostically relevant parameter in colorectal cancer.
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Hawinkels LJAC, Kuiper P, Wiercinska E, Verspaget HW, Liu Z, Pardali E, Sier CFM, ten Dijke P. Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Res 2010; 70:4141-50. [PMID: 20424116 DOI: 10.1158/0008-5472.can-09-4466] [Citation(s) in RCA: 212] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Endoglin is a transforming growth factor-beta coreceptor with a crucial role in angiogenesis. A soluble form of endoglin is present in the circulation, but the role of soluble endoglin (sEndoglin) is poorly understood. In addition, the endoglin shedding mechanism is not known. Therefore, we examined the role of sEndoglin in tumor angiogenesis and the mechanism by which the extracellular domain of endoglin is released from the membrane.In colorectal cancer specimens, we observed high endothelial endoglin protein expression, accompanied with slightly lower sEndoglin levels in the circulation, compared with healthy controls. In vitro analysis using endothelial sprouting assays revealed that sEndoglin reduced spontaneous and vascular endothelial growth factor-induced endothelial sprouting. Human umbilical vascular endothelial cells were found to secrete high levels of sEndoglin. Endoglin shedding was inhibited by matrix metalloproteinase (MMP) inhibitors and MMP-14 short hairpin RNA, indicating MMP-14 as the major endoglin shedding protease. Coexpression of endoglin and membrane-bound MMP-14 led to a strong increase in sEndoglin levels. Endoglin shedding required a direct interaction between endoglin and membrane-localized MMP-14. Using cleavage site mutants, we determined that MMP-14 cleaved endoglin at a site in close proximity to the transmembrane domain. Taken together, this study shows that MMP-14 mediates endoglin shedding, which may regulate the angiogenic potential of endothelial cells in the (colorectal) tumor microenvironment.
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Affiliation(s)
- Lukas J A C Hawinkels
- Departmentsof Molecular Cell Biology, Centre for Biomedical Genetics, Gastroenterology-Hepatology, and Surgery, Leiden University Medical Center, Leiden, the Netherlands.
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31
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Hansen TF, Sørensen FB, Spindler KLG, Olsen DA, Andersen RF, Lindebjerg J, Brandslund I, Jakobsen A. Microvessel density and the association with single nucleotide polymorphisms of the vascular endothelial growth factor receptor 2 in patients with colorectal cancer. Virchows Arch 2010; 456:251-60. [PMID: 20143086 DOI: 10.1007/s00428-009-0878-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2009] [Revised: 11/04/2009] [Accepted: 12/22/2009] [Indexed: 01/22/2023]
Abstract
The measurement of microvessel density (MVD) is a widely accepted method for assessing the neoangiogenetic activity in neoplasia. The aim of the present study was to compare MVD with single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor receptor (VEGFR)-1 and VEGFR-2 genes and, furthermore, with quantitative measurements of the receptors in colorectal cancer (CRC) tissue. Prognosis was also assessed. Blood and tissue were collected from 110 patients surgically resected for CRC. SNPs were analysed from genomic DNA by polymerase chain reaction. MVD was assessed by immunohistochemistry using CD34 and CD105 combined with caldesmon in order to identify also immature vessels. Microvessels were counted in three fields of vision, and the mean MVD was used for statistical analysis. The VEGFR-2 1192 C/T and -604 T/C SNPs were associated with the MVD assessed by CD105. The median MVD score for the 1192 CC genotype was significantly lower compared to the CT + TT genotypes (p = 0.002). The median MVD score for the -604 CC genotype was significantly higher compared to the TT + TC genotypes (p = 0.009). A possible association, although non-significant, was demonstrated for the CD34-positive microvessels. The 1192 CC genotype and the -604 TT + TC genotypes correlated with improved survival. This is the first report on correlations between SNPs in the VEGF receptor genes and MVD in patients with CRC. Associations were shown between two SNPs in the VEGFR-2 gene and the CD105-positive microvessels indicating an impact on neoangiogenesis. Moreover, an association between the SNPs and survival was demonstrated. The clinical implications of these findings need further investigations.
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Affiliation(s)
- Torben Frøstrup Hansen
- Department of Oncology, Danish Colorectal Cancer Group South, Vejle Hospital, Kabbeltoft 25, 7100, Vejle, Denmark.
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Moreira LR, Schenka AA, Filho PL, Lima CSP, Trevisan MAS, Vassallo J. Comparison of blood neoangiogenesis and lymphatic vascularization in colorectal adenomas from patients with and without concomitant colorectal cancer. ACTA ACUST UNITED AC 2009; 42:593-8. [PMID: 19466284 DOI: 10.1590/s0100-879x2009005000004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Accepted: 04/13/2009] [Indexed: 11/21/2022]
Abstract
Blood and lymphatic vessel proliferation is essential for tumor growth and progression. Most colorectal carcinomas develop from adenomas (adenoma-carcinoma sequence) in a process due to accumulation of molecular genetic alterations. About 5% of adenomatous polyps are expected to become malignant, but data on the differential angiogenic patterns of these lesions in patients with and without concomitant cancer are missing. The aim of the present study is to compare the angiogenic and lymphatic patterns of adenomatous polyps from patients with and without sporadic cancer. Thirty adenomatous polyps (15 from patients with another principal malignant lesion, and 15 from patients without cancer) were submitted to immunohistochemical staining for CD105 (marker for neoangiogenesis) and D2-40 (marker for lymphatic endothelium). Microvessel density and total vascular area were determined by computer image analysis to quantify the immunostained and total areas, and to assess the number of microvessels. Adenomas from patients with carcinoma showed significantly higher values of total vascular area determined by immunostaining for CD105 (cutoff value = 4386 microm(2); P = 0.019) and of lymphatic microvessel density determined by immunostaining with D2-40 (cutoff value = 11.5; P = 0.041) when compared with those from patients without cancer. The present data indicate a significant increase in blood microvascular area and in lymphatic microvascular counts in adenomas removed from patients with cancer.
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Affiliation(s)
- L R Moreira
- Laboratório de Patologia Investigativa e Molecular, CIPED, Universidade Estadual de Campinas, 13083-970 Campinas, SP, Brasil
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Combined perioperative plasma endoglin and VEGF-A assessment in colorectal cancer patients. Folia Histochem Cytobiol 2009; 46:487-92. [DOI: 10.2478/v10042-008-0066-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Rubatt JM, Darcy KM, Hutson A, Bean SM, Havrilesky LJ, Grace LA, Berchuck A, Secord AA. Independent prognostic relevance of microvessel density in advanced epithelial ovarian cancer and associations between CD31, CD105, p53 status, and angiogenic marker expression: A Gynecologic Oncology Group study. Gynecol Oncol 2009; 112:469-74. [PMID: 19135712 DOI: 10.1016/j.ygyno.2008.11.030] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Revised: 11/12/2008] [Accepted: 11/17/2008] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The aims of this study were to examine prognostic significance of microvessel density (MVD) in previously-untreated, advanced epithelial ovarian cancer (EOC) and explore associations between MVD and factors that affect angiogenesis. METHODS MVD was determined by immunohistochemical expression of CD31 or CD105 in tumor sections from 106 women treated on GOG randomized phase III trials. Average MVD hotspots were quantified by light microscopy at high power (x400) and categorized as low (<upper quartile) or high (>or=upper quartile). Immunoblot expression of MASPIN, THBS-1, bFGF, VEGF, VEGFR-1 and p53 status (mutation and overexpression) was previously determined. RESULTS Of 106 evaluable cases, 25% exhibited high CD31-MVD (>24.25 vessels/high power field [HPF]) or high CD105-MVD (>19.25 vessels/HPF). After adjusting for age and stratifying by GOG performance status, stage, cell type, grade, debulking status and treatment regimen, high versus low CD105-MVD was associated with increased risk of disease progression (hazard ratio [HR]=1.873; 95% confidence interval [CI]: 1.102-3.184; p=0.020), but not death (HR=1.125; 95% CI: 0.654-1.935; p=0.670) whereas CD31-MVD was not associated with risk of disease progression (HR=1.578; 95% CI=0.918-2.711; p=0.099) or death (HR=1.678; 95% CI=0.957-2.943; p=0.071). CD31-MVD was correlated with CD105-MVD (p=0.001) and MASPIN (p=0.016). Neither CD31-MVD nor CD105-MVD was associated with p53 status, THBS-1, bFGF, VEGF or VEGFR-1. CONCLUSIONS High MVD assessed using CD105, a marker of proliferating endothelial cells and neoangiogenesis, but not CD31 a pan-endothelial marker, appeared to be an independent prognostic factor for worse progression-free survival in women with advanced EOC after adjusting for prognostic clinical covariates.
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Affiliation(s)
- Jennifer M Rubatt
- Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC 27710, USA
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Barresi V, Vitarelli E, Tuccari G, Barresi G. Correlative study of microvessel density and 5-lipoxygenase expression in human sporadic colorectal cancer. Arch Pathol Lab Med 2008; 132:1807-12. [PMID: 18976020 DOI: 10.5858/132.11.1807] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/03/2008] [Indexed: 11/06/2022]
Abstract
CONTEXT 5-Lipoxygenase (5-LO) is an arachidonic acid- metabolizing enzyme, which has been demonstrated to exert a role in colorectal cancer tumorigenesis. Its activity in promoting neoangiogenesis in colorectal malignancies has been also recently theorized on the basis of in vitro studies. OBJECTIVE To investigate whether any correlation existed between 5-LO immunoexpression amount and the quantity of neoangiogenesis, as reflected by microvessel density (MVD) in human sporadic surgically resected colorectal adenocarcinomas. DESIGN A total of 45 formalin-fixed, paraffin-embedded colorectal adenocarcinomas were submitted to the immunohistochemical procedures for 5-LO and CD105, which represent specific markers for neoangiogenesis and which were used in the assessment of MVD. RESULTS CD105-positive, intratumoral, newly formed vessels were present in 45 of 45 cases with variable MVD values. A 5-LO-positive immunohistochemical reaction was also found in 45 of 45 cases. A significantly higher MVD was evident in cases displaying a high 5-LO amount in comparison with those characterized by a low 5-LO expression (28.33 vs 19.44 vessels per mm(2); P = .02). In addition, a positive significant correlation emerged between 5-LO immunoexpression amount and the MVD counts (r = 0.2986, P = .04). CONCLUSIONS Our study demonstrates the existence of a relationship between 5-LO expression and the neoangiogenesis process as reflected by intratumoral MVD in human sporadic colorectal adenocarcinomas, thus suggesting that 5-LO may modulate the formation of blood vessels in these neoplasias.
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Affiliation(s)
- Valeria Barresi
- Department of Human Pathology, University of Messina, Messina, Italy.
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Costa AF, Demasi APD, Bonfitto VLL, Bonfitto JFL, Furuse C, Araújo VC, Metze K, Altemani A. Angiogenesis in salivary carcinomas with and without myoepithelial differentiation. Virchows Arch 2008; 453:359-67. [PMID: 18795324 DOI: 10.1007/s00428-008-0664-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2008] [Revised: 08/18/2008] [Accepted: 08/20/2008] [Indexed: 01/05/2023]
Abstract
To investigate whether salivary carcinomas with and without myoepithelial differentiation could present differences regarding degree of angiogenesis, we compared tumor vascularization between adenoid cystic (31 cases) and epithelial-myoepithelial carcinomas (14) versus mucoepidermoid (37) carcinoma. The expression of peroxiredoxin I was also studied to verify the potential relationship between cellular metabolism and microvascular density. Microvascular density for CD34 and CD105 were significantly lower in carcinomas with myoepithelial differentiation. However, no correlation was found between degree of angiogenesis and amounts of myoepithelial cells. High-grade peroxiredoxin I expression was found in 73.7% of mucoepidermoid carcinomas, whereas 85.1% of carcinomas with myoepithelial differentiation presented low-grade expression. In conclusion, carcinomas with myoepithelial differentiation, regardless of the amounts of myoepithelial cells, are associated to a significantly lower vascular density. The reasons for this lower angiogenic activity remain to be determined but could be related to metabolic characteristics of the cancer cells.
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Affiliation(s)
- A F Costa
- Department of Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, Sao Paulo, Brazil
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Zhang D, Feng XY, Henning TD, Wen L, Lu WY, Pan H, Wu X, Zou LG. MR imaging of tumor angiogenesis using sterically stabilized Gd-DTPA liposomes targeted to CD105. Eur J Radiol 2008; 70:180-9. [PMID: 18541399 DOI: 10.1016/j.ejrad.2008.04.022] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2007] [Revised: 04/17/2008] [Accepted: 04/22/2008] [Indexed: 10/22/2022]
Abstract
AIM To depict tumor angiogenesis via the expression of CD105 in tumor-bearing rats using Gd-DTPA liposomes targeted to CD105 (CD105-Gd-SLs) on MR imaging. MATERIALS AND METHODS Three Gd-DTPA liposomal nanoparticles were prepared in our trial: liposomes entrapping Gd-DTPA (Gd-SLs), Gd-SLs conjugated to immunoglobulins (IgG-Gd-SLs) and CD105-Gd-SLs. Forty glioma-bearing rats were randomized into four groups: (a) Gd-DTPA; (b) Gd-SLs; (c) IgG-Gd-SLs; (d) CD105-Gd-SLs. Axial T1WI MRI images were collected at baseline and repeated at 5, 30, 60 and 120 min post-intravenous injection of Gd-DTPA or liposome. Enhancement features and contrast-to-noise ratio of each group were analyzed. After imaging, tumors were resected for immunohistochemistry and immunofluorescence staining to assess vascularity and angiogenesis. RESULTS The four groups showed different enhancement features. The enhancement area was restricted for group CD105-Gd-SLs, while diffused for the other three. The degree of enhancement over time varied: group Gd-DTPA showed an early contrast enhancement at instant after injection with a peak at 30 min and a decline to baseline values at 60 min. In group CD105-Gd-SLs, the signal intensity (SI) continuously increased over 120 min. In groups IgG-Gd-SLs and Gd-SLs the SI peaked at 60 min, followed by a minor decrease for IgG-Gd-SLs and a rapid decrease for Gd-SLs almost to baseline. Immunohistochemistry and immunofluorescence showed that the enhancement in the CD105-Gd-SLs group resulted mainly from new microvessels. While in the other three groups, mature microvessels and new microvasculature resulted in the enhancement of the tumor. CONCLUSION CD105-Gd-SLs can be used to detect early tumor angiogenesis on MR images. This might provide a means to non-invasively reveal a malignant phenotype of extracerebral F98 tumor and evaluate its progression.
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Affiliation(s)
- Dong Zhang
- Department of Radiology, XinQiao Hospital, Third Military Medical University, ChongQing 400037, PR China
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Yan G, Zhou XY, Cai SJ, Zhang GH, Peng JJ, Du X. Lymphangiogenic and angiogenic microvessel density in human primary sporadic colorectal carcinoma. World J Gastroenterol 2008; 14:101-7. [PMID: 18176970 PMCID: PMC2673372 DOI: 10.3748/wjg.14.101] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the distribution pattern of lymphatic vessels and microvessels in sporadic colorectal carcinoma (SCRC) and their relationship to metastasis and prognosis.
METHODS: The lymphatic vessel density (LVD) and microvessel density (MVD) in tumor tissue obtained from 132 patients with primary SCRC, including 74 with metastases and 58 without metastases, were evaluated by immunohistochemistry using antibodies directed against D2-40 and von Willebrand factor (vWF).
RESULTS: (1) The lymphatic vessels and microvessels at central portions of SCRC often had a reticular architecture with numerous tiny and ill-defined lumina, while those at tumor borders had large and open lumina. The LVD and MVD were both obviously higher in colorectal cancer patients with metastases than in those without (P < 0.001). (2) For each one lymphatic vessel increased, there was a 1.45-fold increase in the risk of metastasis in SCRC. The specificity and sensitivity of LVD in predicting metastasis or non-metastasis in SCRC were 71.62% and 56.90%, respectively, and the corresponding LVD was 5. For each one microvessel increased, there was a 1.11-fold increase in the risk of metastasis in SCRC. The specificity and sensitivity of MVD were 66.22% and 51.72%, respectively. (3) Double labeling immunohistochemistry showed D2-40 immunoreactivity to be specific for lymphatic vessels. (4) Univariate analysis indicated that high LVD, high MVD, as well as co-accounting of high LVD and high MVD were associated with patient’s poor disease-free survival (Puni < 0.05); multivariate analysis indicated that co-accounting of LVD and MVD was an independent prognostic factor of colorectal cancer.
CONCLUSION: D2-40 is a new specific antibody for lymphatic endothelial cells. Lymphogenesis and angiogenesis are commonly seen in SCRC, especially at tumor borders. The detection of LVD and MVD at tumor borders may be useful in predicting metastasis and prognosis in patients with SCRC, and, in particular, co-accounting of LVD and MVD might be a useful prognostic factor in SCRC.
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Abstract
For a tumor to grow beyond a limited volume of 1-2 mm(3), the tumor cells must not only proliferate, but they must be able to induce the growth of new capillary blood vessels from the host. As early as 1971, it was proposed that tumor growth was dependent on angiogenesis; and, that tumor cells and blood vessels composed a highly integrated ecosystem, that endothelial cells could be switched from a resting state to one of rapid growth by a diffusible signal from tumor cells, and that anti-angiogenesis may become an effective anti-cancer therapy. Indeed, now there is considerable indirect and direct evidence to show that tumor growth is angiogenesis dependent, that tumor cells can produce diffusible angiogenic regulatory molecules, and that angiogenesis inhibitors can slow or prevent tumor growth, and that angiogenesis is a relevant target for anti-cancer therapy. Measuring intratumoral microvessel density (iMVD) in vascular "hot spots" has been shown to correlate with aggressive tumor behavior. This chapter reviews the techniques available for measuring iMVD.
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Affiliation(s)
- Noel Weidner
- Department of Pathology, University of California, San Diego, San Diego, California, USA
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Barresi V, Cerasoli S, Vitarelli E, Tuccari G. Density of microvessels positive for CD105 (endoglin) is related to prognosis in meningiomas. Acta Neuropathol 2007; 114:147-56. [PMID: 17594108 DOI: 10.1007/s00401-007-0251-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Revised: 06/04/2007] [Accepted: 06/04/2007] [Indexed: 10/23/2022]
Abstract
Microvessel density (MVD) is considered to be a prognostic marker in many tumours. Nevertheless, conflicting results were achieved regarding its prognostic role in meningiomas when it was quantified through pan-endothelial markers such as CD34, CD31 or Factor VIII. In the present study, MVD was assessed in meningiomas through the specific marker for neo-angiogenesis CD105. Fifty-four formalin fixed, paraffin embedded, surgical cases of meningiomas (WHO 28 grade I and 26 grade II) as well as ten normal leptomeningeal samples were submitted to immunohistochemical analysis for CD105. CD34 immuno-expression was also evaluated on consecutive parallel sections. For each case, MVD was estimated in terms of number of vessels/mm(2). CD105 was not evidenced in normal samples, whereas it was demonstrated in the vessels within 14/28 WHO grade I cases and within 24/26 WHO grade II meningiomas. On the contrary, CD34 antibody stained blood vessels in both normal and neoplastic samples; moreover, in each case, it stained more microvessels than CD105 antibody (25.33 +/- 21.16 vs. 50.72 +/- 26.75). Higher CD105 counts were significantly correlated with higher histological grade and Ki-67 LI > 4%. No statistical significant correlations were encountered between MVD measured by either CD105 and CD34 and sex, age, site of tumour or extent of surgical resection. CD105-MVD, but not CD34-MVD, showed an inverse significant correlation with overall survival and recurrence-free survival. In conclusion, our study suggests the higher specificity of CD105 in comparison to pan-endothelial markers in the evaluation of meningioma neo-angiogenesis, and its higher prognostic significance. CD105 might serve as a target for therapeutic approaches blocking blood supply in meningiomas.
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Affiliation(s)
- Valeria Barresi
- Dipartimento di Patologia Umana, University of Messina, Messina, Italy.
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In vitro angiogenesis and expression of nuclear factor kappaB and VEGF in high and low metastasis cell lines of salivary gland Adenoid Cystic Carcinoma. BMC Cancer 2007; 7:95. [PMID: 17543095 PMCID: PMC1903362 DOI: 10.1186/1471-2407-7-95] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2007] [Accepted: 06/01/2007] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Adenoid cystic carcinoma is a high malignant carcinoma characterized by intensive local invasion and high incidence of distant metastasis. Although many reports have demonstrated that angiogenesis has played an important role in tumor metastasis, the relationship between metastasis characters and angiogenesis ability in high and low metastasis cell lines of Adenoid cystic carcinoma has rarely been reported. The present study aimed to compare the angiogenesis ability of ACC-M (high metastasis) and ACC-2 (low metastasis) cell lines in vitro. Furthermore, the activity of nuclear factor kappaappa B and the expression of vascular endothelial growth factor (VEGF) in ACC-2 and ACC-M were also detected. METHODS Electrophoretic mobility shift assay was used to detect nuclear factor kappaappa B activity. Semi-quantitative RT-PCR was used to quantify the mRNA level of VEGF. Immuofluorescence double staining and semi-quantitative confocal laser scanning analysis was carried out to detect nuclear factor kappaappa B nuclear localization and staining intensity of VEGF. The angiogenesis ability of ACC-M and ACC-2 was compared by an in vitro three-dimensional angiogenic model assay. The vector transfection assay was performed to transfect the PCMV-IkappaBalphaM vector into ACCs cell lines expressing the phosphorylation defective IkappaBalphaM. RESULTS Nuclear factor kappaappa B activity and the rate of nuclear factor kappaappa B nuclear localization in ACC-M was significantly higher than that in ACC-2. Moreover, ACC-M exhibited higher mRNA and protein levels of vascular endothelial growth factor than ACC-2. VEGF mRNA expression was effectively decreased by inhibition of nuclear factor kappaappa B activity. Furthermore, ACC-M could remarkably stimulate the migration and tube formation of endothelial cells and induce The umbilical vein endothelial cells sprouting into the gel matrix. CONCLUSION These results implicated that ACCs cells with higher metastasis feature might present greater angiogenesis ability.
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The associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma. BMC Cancer 2006; 6:255. [PMID: 17067385 PMCID: PMC1635990 DOI: 10.1186/1471-2407-6-255] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2006] [Accepted: 10/26/2006] [Indexed: 12/14/2022] Open
Abstract
Background Maspin, a member of the serpin family, is a suppressor of tumor growth, an inhibitor of angiogenesis and an inducer of apoptosis. Maspin induces apoptosis by increasing Bax, a member of the Bcl-2 family of apoptosis-regulating proteins. In this exploratory study, we investigated the associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma (IHCCA). Methods Twenty-two paraffin-embedded samples were analyzed by immunohistochemical methods using Maspin, Bax and CD34 antibodies. Maspin was scored semiquantitatively (HSCORE). Apoptosis was assessed using an antibody against cleaved caspase-3. Results The strong relationship observed between the expression of Maspin and Bax, indicates that Bax is likely to be the key effector of Maspin-mediated induction of apoptosis as indicated by the activation of cleaved caspase-3. We categorized Maspin HSCORE by calculating the optimal cutpoint. A Maspin HSCORE above the cutpoint was inversely related with tumor dimension, depth of tumor and vascular invasion. Uni/multivariate analysis suggests that a Maspin HSCORE below the cutpoint significantly worsens the patients' prognosis. Tumors with Maspin HSCORE below the cutpoint had a shorter survival (11+/-5 months) than did patients with Maspin HSCORE above the cutpoint (27+/-4 months), whereas Kaplan-Meier analysis and logrank test showed no significant difference in overall survival between the patients. Conclusion The associated expression of Maspin and Bax might delay tumor progression in IHCCA. Maspin above the cutpoint might counteract tumor development by increasing cell apoptosis, and by decreasing tumor mass and cell invasion. The combined expression of Maspin and Bax appears to influence the susceptibility of tumor cholangiocytes to apoptosis and thus may be involved in delaying IHCCA progression.
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Kleespies A. Re: the risk of developing metastatic disease in colorectal cancer is related to CD105-positive vessel count, by Romani AA, Borghetti AF, Del Rio P, et al. J Surg Oncol 2006; 93:435-6. [PMID: 16615147 DOI: 10.1002/jso.20457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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