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Nazir MM, Farzeen I, Zafar S, Fatima S, Zafar N, Ashraf A, Lebelo SL. Biological potential and therapeutic effectiveness with diverse signaling pathways of phyto-product chicoric acid: a comprehensive review with computational evidence. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03931-4. [PMID: 40014130 DOI: 10.1007/s00210-025-03931-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 02/13/2025] [Indexed: 02/28/2025]
Abstract
Chicoric acid (CA), a polyphenolic compound found in chicory (Cichorium intybus), shows potential for the management of a number of diseases due to its antioxidant, anticancer, anti-inflammatory, and insulin-sensitizing properties. Chicory, a perennial member of Asteraceae family, is undoubtedly an underestimated vegetable. Currently, its primary usage is concentrated in India, Greece, Italy, and Poland. This review will concentrate on the potential of chicoric acid in different diseases through a study of the literature and in silico research. A comprehensive search of the literature was conducted using specialized and dedicated search engines. Chicoric acid has an impact on several disease types reported in vitro and in vivo. Chicoric acid has surfaced as a promising neuroprotective agent, anticancer, anti-inflammatory, antidiabetics, and antimicrobial exhibiting a broad range of actions that contribute to health and function. Bioactive compound effects on diseases are examined using network pharmacology (ADME, networking, and docking). KEGG analysis and gene ontology demonstrated that chicoric acid works by interfering with many immune system and cancer pathways. Chicoric acid had the best match with receptor proteins 1PXX and 2YCF, which suited the chemical chicoric acid best, with docking scores of - 8.46 and - 9.4, respectively. To sum up, chicoric acid is a new molecule in the medication development process.
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Affiliation(s)
- Muhammad Muzammil Nazir
- Department of Zoology, Government College University, Allama Iqbal Road, Faisalabad, 38000, Pakistan
| | - Iqra Farzeen
- Department of Zoology, Government College University, Allama Iqbal Road, Faisalabad, 38000, Pakistan
| | - Saima Zafar
- Department of Zoology, Government College University, Allama Iqbal Road, Faisalabad, 38000, Pakistan
| | - Sehrish Fatima
- Department of Zoology, Government College University, Allama Iqbal Road, Faisalabad, 38000, Pakistan
| | - Nimrah Zafar
- Department of Zoology, Government College University, Allama Iqbal Road, Faisalabad, 38000, Pakistan
| | - Asma Ashraf
- Department of Zoology, Government College University, Allama Iqbal Road, Faisalabad, 38000, Pakistan.
| | - Sogolo Lucky Lebelo
- Director of School, Department of Life and Consumer Sciences, College of Agriculture and Environ-Mental Sciences, University of South Africa, Pretoria, South Africa
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Zhu X, Lin SQ, Xie J, Wang LH, Zhang LJ, Xu LL, Xu JG, Lv YB. Biomarkers of lymph node metastasis in colorectal cancer: update. Front Oncol 2024; 14:1409627. [PMID: 39328205 PMCID: PMC11424378 DOI: 10.3389/fonc.2024.1409627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 08/20/2024] [Indexed: 09/28/2024] Open
Abstract
Colorectal cancer (CRC) ranks as the second leading cause of cancer-related deaths globally, trailing only behind lung cancer, and stands as the third most prevalent malignant tumor, following lung and breast cancers. The primary cause of mortality in colorectal cancer (CRC) stems from distant metastasis. Among the various routes of metastasis in CRC, lymph node metastasis predominates, serving as a pivotal factor in both prognostication and treatment decisions for patients. This intricate cascade of events involves multifaceted molecular mechanisms, highlighting the complexity underlying lymph node metastasis in CRC. The cytokines or proteins involved in lymph node metastasis may represent the most promising lymph node metastasis markers for clinical use. In this review, we aim to consolidate the current understanding of the mechanisms and pathophysiology underlying lymph node metastasis in colorectal cancer (CRC), drawing upon insights from the most recent literatures. We also provide an overview of the latest advancements in comprehending the molecular underpinnings of lymph node metastasis in CRC, along with the potential of innovative targeted therapies. These advancements hold promise for enhancing the prognosis of CRC patients by addressing the challenges posed by lymph node metastasis.
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Affiliation(s)
- Xiao Zhu
- Department of Colorectal Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Shui-Quan Lin
- Department of Colorectal Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Jun Xie
- Department of Colorectal Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Li-Hui Wang
- Department of Colorectal Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Li-Juan Zhang
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ling-Ling Xu
- Department of Endocrinology and Metabolism, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jian-Guang Xu
- Department of Gastroenterology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
| | - Yang-Bo Lv
- Department of Colorectal Surgery, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China
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Mondal DK, Xie C, Pascal GJ, Buraschi S, Iozzo RV. Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression. Proc Natl Acad Sci U S A 2024; 121:e2317760121. [PMID: 38652741 PMCID: PMC11067011 DOI: 10.1073/pnas.2317760121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a prosurvival program and to sustain a proangiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we identified that decorin down-regulated a cluster of tumor-associated genes involved in lymphatic vessel (LV) development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of LVs, were markedly suppressed at both the mRNA and protein levels, and this suppression correlated with a significant reduction in tumor LVs. We further identified that soluble decorin, but not its homologous proteoglycan biglycan, inhibited LV sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with vascular endothelial growth factor receptor 3 (VEGFR3), the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we identified that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a biological factor with antilymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
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Affiliation(s)
- Dipon K. Mondal
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Christopher Xie
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Gabriel J. Pascal
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Simone Buraschi
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
| | - Renato V. Iozzo
- Department of Pathology and Genomic Medicine, and the Translational Cellular Oncology Program, Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA19107
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Liu J, Miao G, Deng L, Zhou G, Yang C, Rao S, Liu L, Zeng M. Should the Baseline MRI Staging Criteria Differentiate Between Mucinous and Classical Rectal Adenocarcinoma? Acad Radiol 2024; 31:1378-1387. [PMID: 37949701 DOI: 10.1016/j.acra.2023.10.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/08/2023] [Accepted: 10/16/2023] [Indexed: 11/12/2023]
Abstract
RATIONALE AND OBJECTIVES To compare baseline MR imaging features for pre-treatment staging between rectal mucinous adenocarcinoma (RMAC) and rectal classical adenocarcinoma (RCAC), and to investigate whether the subtype of mucinous carcinoma influences MRI evaluation criteria and high-risk tumors identifying. METHODS A total of 306 patients who underwent surgical rectal cancer resection were retrospectively reviewed in the study. MR imaging parameters of the primary tumor and lymph nodes (LNs) were compared between two subtypes. Logistic regression and receiver operating characteristic analyses were performed to test significant associations between LN imaging parameters and malignant LN status in RMAC and RCAC, respectively. RESULTS The length of mucinous tumors was larger than RCAC tumors in pT3 and pT4 stage. For pN0 patients, the long and short diameters of the largest LN on MRI were more likely to be larger in RCAC than RMAC. For pN+ patients, the proportion of LNs exhibiting internal heterogeneity in RMAC was obviously greater than that in RCAC. The best cut-off value of the largest short diameter of malignant LNs was 6.05 mm for RMAC and 8.05 mm for RCAC. And the highest AUC for predicting LNs metastases based on the largest short diameter was 0.794 for RMAC using 6 mm size cut-off, and 0.667 for RCAC using 8 mm cut-off. CONCLUSION The imaging features that were associated with LN metastases were different between RMAC and RCAC, and different size criteria of LNs was suggested to distinguish high-risk tumors. Clinicians should stay vigilant of LN status and take histologic subtypes into consideration before assigning clinical strategies.
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Affiliation(s)
- Jingjing Liu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.); Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., G.Z., C.Y., S.R., L.L., M.Z.); Shanghai Institute of Medical Imaging, Shanghai, China (J.L., G.Z., C.Y., S.R., L.L., M.Z.)
| | - Gengyun Miao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.); Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., G.Z., C.Y., S.R., L.L., M.Z.)
| | - Lamei Deng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.)
| | - Guofeng Zhou
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.); Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., G.Z., C.Y., S.R., L.L., M.Z.); Shanghai Institute of Medical Imaging, Shanghai, China (J.L., G.Z., C.Y., S.R., L.L., M.Z.)
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.); Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., G.Z., C.Y., S.R., L.L., M.Z.); Shanghai Institute of Medical Imaging, Shanghai, China (J.L., G.Z., C.Y., S.R., L.L., M.Z.)
| | - Shengxiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.); Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., G.Z., C.Y., S.R., L.L., M.Z.); Shanghai Institute of Medical Imaging, Shanghai, China (J.L., G.Z., C.Y., S.R., L.L., M.Z.)
| | - Liheng Liu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.); Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., G.Z., C.Y., S.R., L.L., M.Z.); Shanghai Institute of Medical Imaging, Shanghai, China (J.L., G.Z., C.Y., S.R., L.L., M.Z.)
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., L.D., G.Z., C.Y., S.R., L.L., M.Z.); Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China (J.L., G.M., G.Z., C.Y., S.R., L.L., M.Z.); Shanghai Institute of Medical Imaging, Shanghai, China (J.L., G.Z., C.Y., S.R., L.L., M.Z.).
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Fan S, Qi M, Qi Q, Miao Q, Deng L, Pan J, Qiu S, He J, Huang M, Li X, Huang J, Lin J, Lyu W, Deng W, He Y, Liu X, Gao L, Zhang D, Ye W, Chen M. Targeting FAP α-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis. Acta Pharm Sin B 2024; 14:682-697. [PMID: 38322324 PMCID: PMC10840431 DOI: 10.1016/j.apsb.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 09/18/2023] [Accepted: 10/24/2023] [Indexed: 02/08/2024] Open
Abstract
Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.
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Affiliation(s)
- Shuran Fan
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Ming Qi
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Qi Qi
- School of Medicine, Jinan University, Guangzhou 510632, China
| | - Qun Miao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Lijuan Deng
- School of Traditional Chinese Medicine, Jinan University, Guangzhou 510630, China
| | - Jinghua Pan
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Shenghui Qiu
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Jiashuai He
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Maohua Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaobo Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jie Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Jiapeng Lin
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Wenyu Lyu
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Weiqing Deng
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yingyin He
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xuesong Liu
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Lvfen Gao
- The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Dongmei Zhang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Wencai Ye
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Minfeng Chen
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
- State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
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Liu H, Shi H, Sun Y. Identification of a novel lymphangiogenesis signature associated with immune cell infiltration in colorectal cancer based on bioinformatics analysis. BMC Med Genomics 2024; 17:2. [PMID: 38167072 PMCID: PMC10763205 DOI: 10.1186/s12920-023-01781-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 12/16/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND Lymphangiogenesis plays an important role in tumor progression and is significantly associated with tumor immune infiltration. However, the role and mechanisms of lymphangiogenesis in colorectal cancer (CRC) are still unknown. Thus, the objective is to identify the lymphangiogenesis-related genes associated with immune infiltration and investigation of their prognosis value. METHODS mRNA expression profiles and corresponding clinical information of CRC samples were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The lymphangiogenesis-related genes (LymRGs) were collected from the Molecular Signatures database (MSigDB). Lymphangiogenesis score (LymScore) and immune cell infiltrating levels were quantified using ssGSEA. LymScore) and immune cell infiltrating levels-related hub genes were identified using weighted gene co-expression network analysis (WGCNA). Univariate Cox and LASSO regression analyses were performed to identify the prognostic gene signature and construct a risk model. Furthermore, a predictive nomogram was constructed based on the independent risk factor generated from a multivariate Cox model. RESULTS A total of 1076 LymScore and immune cell infiltrating levels-related hub genes from three key modules were identified by WGCNA. Lymscore is positively associated with natural killer cells as well as regulator T cells infiltrating. These modular genes were enriched in extracellular matrix and structure, collagen fibril organization, cell-substrate adhesion, etc. NUMBL, TSPAN11, PHF21A, PDGFRA, ZNF385A, and RIMKLB were eventually identified as the prognostic gene signature in CRC. And patients were divided into high-risk and low-risk groups based on the median risk score, the patients in the high-risk group indicated poor survival and were predisposed to metastasis and advanced stages. NUMBL and PHF21A were upregulated but PDGFRA was downregulated in tumor samples compared with normal samples in the Human Protein Atlas (HPA) database. CONCLUSION Our finding highlights the critical role of lymphangiogenesis in CRC progression and metastasis and provides a novel gene signature for CRC and novel therapeutic strategies for anti-lymphangiogenic therapies in CRC.
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Affiliation(s)
- Hong Liu
- Department of General Surgery, Wuxi Fifth People's Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu, China
| | - Huiwen Shi
- Department of General Surgery, No.971 Hospital of PLA Navy, Qingdao, China
| | - Yinggang Sun
- Department of General Surgery, The 960th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Jinan, China.
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Thapa K, Khan H, Kaur G, Kumar P, Singh TG. Therapeutic targeting of angiopoietins in tumor angiogenesis and cancer development. Biochem Biophys Res Commun 2023; 687:149130. [PMID: 37944468 DOI: 10.1016/j.bbrc.2023.149130] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/12/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
The formation and progression of tumors in humans are linked to the abnormal development of new blood vessels known as neo-angiogenesis. Angiogenesis is a broad word that encompasses endothelial cell migration, proliferation, tube formation, and intussusception, as well as peri-EC recruitment and extracellular matrix formation. Tumor angiogenesis is regulated by angiogenic factors, out of which some of the most potent angiogenic factors such as vascular endothelial growth factor and Angiopoietins (ANGs) in the body are produced by macrophages and other immune cells within the tumor microenvironment. ANGs have a distinct function in tumor angiogenesis and behavior. ANG1, ANG 2, ANG 3, and ANG 4 are the family members of ANG out of which ANG2 has been extensively investigated owing to its unique role in modifying angiogenesis and its tight association with tumor progression, growth, and invasion/metastasis, which makes it an excellent candidate for therapeutic intervention in human malignancies. ANG modulators have demonstrated encouraging outcomes in the treatment of tumor development, either alone or in conjunction with VEGF inhibitors. Future development of more ANG modulators targeting other ANGs is needed. The implication of ANG1, ANG3, and ANG4 as probable therapeutic targets for anti-angiogenesis treatment in tumor development should be also evaluated. The article has described the role of ANG in tumor angiogenesis as well as tumor growth and the treatment strategies modulating ANGs in tumor angiogenesis as demonstrated in clinical studies. The pharmacological modulation of ANGs and ANG-regulated pathways that are responsible for tumor angiogenesis and cancer development should be evaluated for the development of future molecular therapies.
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Affiliation(s)
- Komal Thapa
- Chitkara School of Pharmacy, Chitkara University, 174103, Himachal Pradesh, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, 140401, Punjab, India
| | - Gagandeep Kaur
- Chitkara School of Pharmacy, Chitkara University, 174103, Himachal Pradesh, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, 151401, Bathinda, India
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Mondal DK, Xie C, Buraschi S, Iozzo RV. Decorin suppresses tumor lymphangiogenesis: A mechanism to curtail cancer progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.28.555187. [PMID: 37693608 PMCID: PMC10491239 DOI: 10.1101/2023.08.28.555187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a pro-survival program and to sustain a pro-angiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we discovered that decorin downregulated a cluster of tumor-associated genes involved in lymphatic vessel development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of lymphatic vessels, were markedly suppressed at both the mRNA and protein levels and this suppression correlated with a significant reduction in tumor lymphatic vessels. We further discovered that soluble decorin, but not its homologous proteoglycan biglycan, inhibited lymphatic vessel sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with VEGFR3, the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we discovered that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a new biological factor with anti-lymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.
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9
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Shi C, Chen W, Davis R, Morse MA. Venous Invasion in Pancreatic Neuroendocrine Tumors Is Independently Associated With Disease-free Survival and Overall Survival. Am J Surg Pathol 2023; 47:678-685. [PMID: 37017316 DOI: 10.1097/pas.0000000000002038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2023]
Abstract
In this study, we evaluated venous invasion and its association with survival in patients with resected pancreatic neuroendocrine tumor (PanNET). Surgical Pathology Archives were searched for pancreatectomies performed for PanNET between October 1, 2005, and December 31, 2019. Hematoxylin and eosin (H&E)-stained slides were evaluated for venous invasion, and Movat's stain was performed in all cases with no venous invasion detected on H&E stains. Pathology reports and electronic medical records were also reviewed. Venous invasion was identified in 23 of 145 (15.9%) cases on H&E stains, and Movat's stain identified additional 34 cases with venous invasion (39.3% overall). Orphan arteries with adjacent well-defined tumor nodules or subtle hyalinizing nodules in hyalinizing tumors are highly specific for venous invasion. In stage I-III cases (n=122), venous invasion was associated with larger tumor size, higher World Health Organization (WHO) tumor grade, perineural invasion, extrapancreatic extension, lymph node metastasis, and liver metastasis ( P <0.05). In univariate analyses, tumor size, WHO grade, venous invasion, perineural invasion, T stage, and lymph node metastasis all correlated with disease-free survival; however, only venous invasion was associated with worse disease-free survival in multivariate analyses ( P <0.01). In all-stage cases, venous invasion was the only attributor associated with worse overall survival in multivariate analyses ( P =0.03). In summary, venous invasion in PanNET can be histologically subtle, and Movat's stain can greatly increase the detection rate. More importantly, enhanced venous invasion by Movat's stain correlates independently with disease-free survival in patients with stage I-III tumors and overall survival in all-stage patients.
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Affiliation(s)
| | | | | | - Michael A Morse
- Medicine, Medical Oncology, Duke University Medical Center, Durham, NC
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Sakamoto K, Ogawa K, Tamura K, Honjo M, Funamizu N, Takada Y. Prognostic Role of the Intrahepatic Lymphatic System in Liver Cancer. Cancers (Basel) 2023; 15:2142. [PMID: 37046803 PMCID: PMC10093457 DOI: 10.3390/cancers15072142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Although several prognosticators, such as lymph node metastasis (LNM), were reported for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the prognostic impact of intrahepatic lymphatic vessel invasion (LVI) in liver cancer has rarely been reported. We sought to clarify the prognostic impact of intrahepatic lymphatic system involvement in liver cancer. We systematically reviewed retrospective studies that described LVI and clinical outcomes of liver cancer and also included studies that investigated tumor-associated lymphangiogenesis. We conducted a meta-analysis using RevMan software (version 5.4.1; Cochrane Collaboration, Oxford, UK). The prognostic impact of intrahepatic LVI in HCC was not reported previously. However, tumor-associated lymphangiogenesis reportedly correlates with prognosis after HCC resection. The prognostic impact of intrahepatic LVI was reported severally for ICC and a meta-analysis showed that overall survival was poorer in patients with positive LVI than with negative LVI after resection of ICC. Lymphangiogenesis was also reported to predict unfavorable prognosis in ICC. Regarding colorectal liver metastases, LVI was identified as a poor prognosticator in a meta-analysis. A few reports showed correlations between LVI/lymphangiogenesis and LNM in liver cancer. LVI and lymphangiogenesis showed worse prognostic impacts for liver cancer than their absence, but further study is needed.
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Affiliation(s)
- Katsunori Sakamoto
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, 454 Kou, Shitsukawa, Toon 791-0295, Ehime, Japan
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11
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钟 江, 王 洁, 叶 秀, 范 松, 王 友, 陈 伟. [High expression of CCBE1 in adjacent tissues of tongue squamous cell carcinoma is correlated with pericancerous lymphatic vessel proliferation and poor 5-year survival outcomes]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1545-1551. [PMID: 36329590 PMCID: PMC9637508 DOI: 10.12122/j.issn.1673-4254.2022.10.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVE To examine the correlation of CCBE1 expression in adjacent tissues of tongue squamous cell carcinoma (TSCC) with pericancerous lymphatic vessel proliferation, cervical lymph node metastasis and survival outcomes of the patients. METHODS Lymphatic vessel density was quantified in pericancerous tissue sections of 44 cases of cT1-2N0 TSCC using D2-40 as the lymphatic vessel endothelial marker for calibration and counting of the lymphatic vessels. Of these 44 cases, 22 showed a relatively low lymphatic vessel density (group A) and the other 22 had a high lymphatic vessel density (group B), and the expression levels of CCBE1 in the adjacent tissues determined using immunohistochemistry, immunofluorescence assay and Western blotting were compared between the two groups. The expression level of CCBE1 was also measured in another 90 patients with TSCC using immunohistochemistry, and all the patients were followed up for their survival outcomes. RESULTS Immunohistochemistry and Western blotting showed a significantly lower rate of high CCBE1 expression in group A than in group B (P < 0.05). Immunofluorescence assay showed co-localization of CCBE1 and D2-40 in the adjacent tissues of TSCC. In the 90 TSCC patients with complete follow-up data, a high expression of CCBE1 was found to correlate with lymph node metastasis and a poor 5-year survival outcomes of the patients (P < 0.05). CONCLUSION A high expression of CCBE1 in the adjacent tissues of TSCC is closely related with pericancerous lymphatic vessel proliferation, cervical lymph node metastasis and a poor 5-year survival of the patients, suggesting the value of CCBE1 as a potential prognostic predictor for TSCC.
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Affiliation(s)
- 江龙 钟
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 洁琪 王
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 秀华 叶
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 松 范
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 友元 王
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - 伟良 陈
- />中山大学孙逸仙纪念医院口腔颌面外科，广东 广州 510120Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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12
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Masood F, Bhattaram R, Rosenblatt MI, Kazlauskas A, Chang JH, Azar DT. Lymphatic Vessel Regression and Its Therapeutic Applications: Learning From Principles of Blood Vessel Regression. Front Physiol 2022; 13:846936. [PMID: 35392370 PMCID: PMC8980686 DOI: 10.3389/fphys.2022.846936] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 02/25/2022] [Indexed: 02/03/2023] Open
Abstract
Aberrant lymphatic system function has been increasingly implicated in pathologies such as lymphedema, organ transplant rejection, cardiovascular disease, obesity, and neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. While some pathologies are exacerbated by lymphatic vessel regression and dysfunction, induced lymphatic regression could be therapeutically beneficial in others. Despite its importance, our understanding of lymphatic vessel regression is far behind that of blood vessel regression. Herein, we review the current understanding of blood vessel regression to identify several hallmarks of this phenomenon that can be extended to further our understanding of lymphatic vessel regression. We also summarize current research on lymphatic vessel regression and an array of research tools and models that can be utilized to advance this field. Additionally, we discuss the roles of lymphatic vessel regression and dysfunction in select pathologies, highlighting how an improved understanding of lymphatic vessel regression may yield therapeutic insights for these disease states.
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13
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Bae JH, Kim JH, Kye BH, Al-Sawat A, Lee CS, Han SR, Lee IK, Lee SH, Lee YS. Comparison of Vascular Invasion With Lymph Node Metastasis as a Prognostic Factor in Stage I-III Colon Cancer: An Observational Cohort Study. Front Surg 2021; 8:773019. [PMID: 34859041 PMCID: PMC8631288 DOI: 10.3389/fsurg.2021.773019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/18/2021] [Indexed: 11/17/2022] Open
Abstract
Purpose: This study aimed to evaluate the prognostic impact of vascular invasion (VI) in comparison with that of lymph node metastasis (LNM) in non-metastatic colon cancer. Methods: Patients who underwent curative surgery for stage I-III colon cancer were divided into four groups depending on the status of VI and LNM (Group I: VI-/LNM-; Group II: VI+/LNM-; Group III: VI-/LNM+; Group IV: VI+/LNM+). Group III was subdivided according to the nodal (N) stage (Group IIIA: VI-/N1; Group IIIB: VI-/N2). Oncological outcomes were compared between Groups II and III. Results: In total, 793 non-metastatic colon cancer patients were included. Group II [hazard ratio (HR) 2.34, 1.01–5.41] and Group III (HR 1.91, 1.26–2.89) were independently associated with poor disease-free survival (DFS). The 5-year DFS rates were comparable in Groups II (71.6%) and III (72.5%) (P = 0.637). When Group III was subdivided into Groups IIIA and IIIB, DFS deteriorated in the following order: Groups IIIA, II, and IIIB. The 5-year DFS rates were 79.7, 71.6, and 61.4% in Groups IIIA, II, and IIIB, respectively. Group II had a tendency toward early recurrence. The 1- and 2-year DFS rates were 76.3 and 71.6% in Group II and 88.3 and 79.8% in Group III, respectively (P = 0.067 and 0.247). All recurrences in Group II were distant metastases. Conclusion: VI is a prognostic factor as significant as LNM and may be a stronger prognostic factor than N1 stage in non-metastatic colon cancer. Furthermore, a potential association was observed between VI and recurrence patterns, such as early recurrence and distant metastasis.
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Affiliation(s)
- Jung Hoon Bae
- Division of Colorectal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ji Hoon Kim
- Division of Colorectal Surgery, Department of Surgery, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, South Korea
| | - Bong-Hyeon Kye
- Division of Colorectal Surgery, Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon-Si, South Korea
| | - Abdullah Al-Sawat
- Department of Surgery, College of Medicine, Taif University, Taif, Saudi Arabia
| | - Chul Seung Lee
- Division of Colorectal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung-Rim Han
- Division of Colorectal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - In Kyu Lee
- Division of Colorectal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Yoon Suk Lee
- Division of Colorectal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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Yardımcı AH, Koçak B, Turan Bektaş C, Sel İ, Yarıkkaya E, Dursun N, Bektaş H, Usul Afşar Ç, Gürsu RU, Kılıçkesmez Ö. Tubular gastric adenocarcinoma: machine learning-based CT texture analysis for predicting lymphovascular and perineural invasion. ACTA ACUST UNITED AC 2020; 26:515-522. [PMID: 32990246 DOI: 10.5152/dir.2020.19507] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE Lymphovascular invasion (LVI) and perineural invasion (PNI) are associated with poor prognosis in gastric cancers. In this work, we aimed to investigate the potential role of computed tomography (CT) texture analysis in predicting LVI and PNI in patients with tubular gastric adenocarcinoma (GAC) using a machine learning (ML) approach. METHODS Sixty-eight patients who underwent total gastrectomy with curative (R0) resection and D2-lymphadenectomy were included in this retrospective study. Texture features were extracted from the portal venous phase CT images. Dimension reduction was first done with a reproducibility analysis by two radiologists. Then, a feature selection algorithm was used to further reduce the high-dimensionality of the radiomic data. Training and test splits were created with 100 random samplings. ML-based classifications were done using adaptive boosting, k-nearest neighbors, Naive Bayes, neural network, random forest, stochastic gradient descent, support vector machine, and decision tree. Predictive performance of the ML algorithms was mainly evaluated using the mean area under the curve (AUC) metric. RESULTS Among 271 texture features, 150 features had excellent reproducibility, which were included in the further feature selection process. Dimension reduction steps yielded five texture features for LVI and five for PNI. Considering all eight ML algorithms, mean AUC and accuracy ranges for predicting LVI were 0.777-0.894 and 76%-81.5%, respectively. For predicting PNI, mean AUC and accuracy ranges were 0.482-0.754 and 54%-68.2%, respectively. The best performances for predicting LVI and PNI were achieved with the random forest and Naive Bayes algorithms, respectively. CONCLUSION ML-based CT texture analysis has a potential for predicting LVI and PNI of the tubular GACs. Overall, the method was more successful in predicting LVI than PNI.
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Affiliation(s)
- Aytül Hande Yardımcı
- Department of Radiology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Burak Koçak
- Department of Radiology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Ceyda Turan Bektaş
- Department of Radiology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - İpek Sel
- Department of Radiology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Enver Yarıkkaya
- Department of Pathology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Nevra Dursun
- Department of Pathology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Hasan Bektaş
- Department of General Surgery, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Çiğdem Usul Afşar
- Department of Medical Oncology, Acıbadem Mehmet Ali Aydınlar University, Medical Faculty, Acıbadem Bakırköy Hospital, İstanbul, Turkey
| | - Rıza Umar Gürsu
- Department of Medical Oncology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Özgür Kılıçkesmez
- Department of Radiology, İstanbul Training and Research Hospital, İstanbul, Turkey
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Three-dimension amide proton transfer MRI of rectal adenocarcinoma: correlation with pathologic prognostic factors and comparison with diffusion kurtosis imaging. Eur Radiol 2020; 31:3286-3296. [PMID: 33125558 DOI: 10.1007/s00330-020-07397-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 09/23/2020] [Accepted: 10/08/2020] [Indexed: 01/10/2023]
Abstract
OBJECTIVES To investigate the utility of 3D amide proton transfer (APT) MRI in predicting pathologic factors for rectal adenocarcinoma, in comparison with diffusion kurtosis imaging. METHODS Sixty-one patients with rectal adenocarcinoma were enrolled in this prospective study. 3D APT and diffusion kurtosis imaging (DKI) were performed. Mean APT-weighted signal intensity (APTw SI), mean kurtosis (MK), mean diffusivity (MD), and ADC values of tumors were calculated on these maps. Pathological analysis included WHO grades, pT stages, pN stages, and extramural venous invasion (EMVI) status. Student's t test, Spearman correlation, and receiver operating characteristics (ROC) analysis were used for statistical analysis. RESULTS High-grade rectal adenocarcinoma showed significantly higher mean APTw SI and MK values (2.771 ± 0.384 vs 2.108 ± 0.409, 1.167 ± 0.216 vs 1.045 ± 0.175, respectively; p < 0.05). T3 rectal adenocarcinoma demonstrated higher mean APTw SI and MK than T2 tumors (2.433 ± 0.467 vs 1.900 ± 0.302, p < 0.05). No kurtosis, diffusivity, and ADC differences were found between T2 and T3 tumors. Tumors with lymph node metastasis and EMVI involvement showed significantly higher mean APTw SI, MK. No difference was found in diffusivity and ADC between pN0 and pN1-2 groups, and EMVI-negative and EMVI-positive statuses. Mean APTw SI exhibited a significantly high positive correlation with WHO grades, demonstrating 92.31% sensitivity and 79.17% specificity for distinguishing low- from high-grade rectal adenocarcinoma, providing a better diagnostic capacity than MK, MD, and mean ADC values. CONCLUSION 3D-APT could serve as a non-invasive biomarker for evaluating prognostic factors of rectal adenocarcinoma. KEY POINTS • Mean APTw SI was significantly higher in high-grade compared to low-grade rectal adenocarcinoma. • Mean APTw SI was significantly higher in T3 stage rectal adenocarcinoma, with lymph node metastasis, or in EMVI-positive status. • APTw SI exhibited greater diagnostic capability in discriminating low-grade from high-grade rectal adenocarcinoma, compared with kurtosis, diffusivity, and ADC.
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Ruffolo C, Ferrara F, Trevellin E, Cataldo I, Fornasier C, Pozza A, Campo Dell'Orto M, Angriman I, Dei Tos AP, Bardini R, Massani M, Kotsafti A, Scarpa M. Can Vascular Endothelial Growth Factors and CD34 Expression Implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) Classification in Colorectal Polypoid Lesion Diagnosis? Eur Surg Res 2020; 61:72-82. [PMID: 33080605 DOI: 10.1159/000510266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 07/13/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) is a subfamily of growth factors involved in angiogenesis; CD34+ cells are normally found in endothelial progenitor cells and endothelial cells of blood vessels. Colonic adenomatous polyps may not always be completely removable endoscopically, and a preoperative diagnosis might still be necessary. The aim of the study was to evaluate whether VEGF-A, VEGF-C and CD34 mRNA expression along colorectal carcinogenesis steps can implement NICE (Narrow-Band Imaging International Colorectal Endoscopic) classification in the diagnosis of malignancy in colorectal polypoid lesions. METHODS Seventy-one subjects with colonic adenoma or cancer who underwent screening narrow-band imaging (NBI) colonoscopy were prospectively enrolled in the MICCE1 project (Treviso center). Polyps were classified according to the NICE classification. Real-time RT-PCR for VEGF-A, VEGF-C and CD34 mRNA expression was performed. Nonparametric statistics, receiver-operating characteristic curve analysis and logistic multiple regression analysis were used. RESULTS VEGF-A and CD34 mRNA expression was significantly higher in sessile adenomas than in polypoid ones (p < 0.001 and p = 0.01, respectively). VEGF-A, VEGF-C and CD34 mRNA expression was significantly higher in adenocarcinoma than in adenoma (p = 0.01, p = 0.01 and p = 0.01, respectively). The accuracy of VEGF-A, VEGF-C and CD34 mRNA expression for prediction of malignancy was 0.79 (95% CI 0.65-0.90), 0.81 (95% CI 0.66-0.91) and 0.80 (95% CI 0.65-0.90), respectively, while the accuracy of the NICE classification was 0.85 (95% CI 0.72-0.94). The determination coefficient R2, which indicates the amount of the variability explained by a regression model, for NICE classification alone was 0.24 (p < 0.001). A regression model that included NICE classification and VEGF-C mRNA expression showed an R2 = 0.39 as well as a model including NICE classification and CD34 mRNA levels. CONCLUSIONS This study demonstrated that VEGF-C and CD34 mRNA levels might be useful to stratify colorectal polyps in different risk of progression classes by implementing the accuracy of the NICE classification. Studies on in vivo detection of these markers are warranted.
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Affiliation(s)
- Cesare Ruffolo
- General Surgery Unit, Padova University Hospital, Padova, Italy,
| | - Francesco Ferrara
- Gastroenterology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | - Ivana Cataldo
- Pathology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Caterina Fornasier
- Department of Surgery, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Anna Pozza
- Department of Surgery, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Marta Campo Dell'Orto
- Pathology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Imerio Angriman
- General Surgery Unit, Padova University Hospital, Padova, Italy
| | - Angelo Paolo Dei Tos
- Pathology Unit, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.,Pathology Unit, University of Padova, Padova, Italy
| | - Romeo Bardini
- General Surgery Unit, Padova University Hospital, Padova, Italy
| | - Marco Massani
- Department of Surgery, Cà Foncello Regional Hospital, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Andromachi Kotsafti
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy
| | - Marco Scarpa
- General Surgery Unit, Padova University Hospital, Padova, Italy
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Hong KD, Lee Y, Kim BH, Lee SI, Moon HY. Expression of GLI1 Correlates with Expression of Lymphangiogenesis Proteins, Vascular Endothelial Growth Factor C and Vascular Endothelial Growth Factor Receptor 3, in Colorectal Cancer. Am Surg 2020. [DOI: 10.1177/000313481307900232] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Aberrant activation of the hedgehog (Hh) signaling pathway is associated with tumorigenesis in various tissues. In colorectal cancer (CRC), evidence for Hh activation is inconsistent, and the relationship between the Hh signaling pathway and lymphangiogenesis has not been studied. The aim of this study was to determine the relationship between Hh signaling and lymphangio-genesis and the association of this relationship with lymph node metastasis in CRC. We investigated 189 patients who underwent curative surgical resection for CRC between 2002 and 2004 at Korea University Guro Hospital. Paraffin-embedded specimens of colorectal adenocarcinoma and adjacent normal mucosa were evaluated. Immunohistochemical staining for Sonic hedgehog (Shh), Gli1, vascular endothelial growth factor C (VEGFC), and VEGF receptor 3 (VEGFR3) was performed for each specimen. Tumor specimen showed significantly strong staining of Shh, Gli1, VEGFC, and VEGFR3 compared with a normal specimen. Shh expression was not associated with Gli1 expression. Gli1 expression correlated positively with VEGFC and VEGFR3 expression ( P < 0.05 in both) but not with lymph node metastasis. Activation of the Hh signaling pathway associated with Gli1 promotes expression of lymphangiogenesis proteins, VEGFC and VEGFR3, in CRC. Further studies are necessary to determine the association of this relationship with lymph node metastasis in CRC.
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Affiliation(s)
- Kwang Dae Hong
- Departments of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Youngseok Lee
- Pathology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Baek-Hui Kim
- Pathology, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sun Il Lee
- Departments of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hong Young Moon
- Departments of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
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18
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Woodham BL, Chmelo J, Donohoe CL, Madhavan A, Phillips AW. Prognostic Significance of Lymphatic, Venous and Perineural Invasion After Neoadjuvant Chemotherapy in Patients with Gastric Adenocarcinoma. Ann Surg Oncol 2020; 27:3296-3304. [PMID: 32219726 PMCID: PMC7410853 DOI: 10.1245/s10434-020-08389-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Indexed: 12/28/2022]
Abstract
Background The significance of perineural (PNI), lymphatic (LI) and venous invasion (VI) in gastric cancer patients who have received neoadjuvant chemotherapy is unclear. The aim of this study is to determine the incidence and prognostic significance of LI, VI and PNI in these patients. Patients and Methods Consecutive patients treated with neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy were reviewed. Presence of LI, VI and PNI was recorded and correlated with clinical outcomes. Results A total of 243 patients underwent gastrectomy after neoadjuvant therapy for gastric adenocarcinoma. LI was identified in 129 (53%), VI in 107 (44%) and PNI in 116 (48%) of patients. Presence of LI (HR, 2.95, CI 1.91–4.56), VI (HR, 2.66, CI 1.78–3.98) and PNI (HR, 3.85, CI 2.49–5.95) was associated with poorer survival (all p < 0.001). Multivariable analysis revealed that ypT stage (HR, 1.35, CI 1.05–1.74), ypN stage (HR, 1.53, CI 1.28–1.83) and PNI (HR, 2.11, CI 1.31–3.42) were independent predictors of survival. Conclusions LI, VI and PNI are associated with poorer survival, with PNI having prognostic significance independent of lymph node status. These factors may be useful for further prognostication, in particular when multiple factors are present, and appear especially useful for prognostic stratification in patients with no nodal involvement.
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Affiliation(s)
- Benjamin L Woodham
- Northern Oesophagogastric Unit, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Jakub Chmelo
- Northern Oesophagogastric Unit, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Claire L Donohoe
- Northern Oesophagogastric Unit, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Anantha Madhavan
- Northern Oesophagogastric Unit, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Alexander W Phillips
- Northern Oesophagogastric Unit, Royal Victoria Infirmary, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK. .,School of Medical Education, Newcastle University, Newcastle upon Tyne, UK.
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Ma CH, Hwang DW, Song KB, Kim SC, Shin SH, Lee JH. Prognostic factors predicting survival rate over 10 years of patients with intrahepatic cholangiocarcinoma after hepatic resection. Ann Surg Treat Res 2020; 98:116-123. [PMID: 32158731 PMCID: PMC7052393 DOI: 10.4174/astr.2020.98.3.116] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/27/2019] [Accepted: 01/11/2020] [Indexed: 02/06/2023] Open
Abstract
Purpose Hepatic resection is considered as the optimal treatment for intrahepatic cholangiocarcinoma (IHCC); however, the survival rate after resection is low and the analysis of long-term (≥10 years) survivors is rare. This study aims to analyze the clinicopathological factors affecting the long-term survival of patients with IHCC. Methods Between January 2003 and December 2012, a single-institution cohort of 429 patients who underwent hepatic resection for IHCC were reviewed retrospectively. Surgical results, recurrence, and survival rates were investigated, and multivariate analyses were performed to identify prognostic factors. Results The overall 1- , 3- , 5- and 10-year survival rates of patients were 76.5%, 44.1%, 33.3%, and 25.1%, respectively. Multivariate analysis showed that the serum CA 19-9 level (≥38 U/mL) (P < 0.001), lymph node (LN) metastasis (P = 0.001), and lymphovascular invasion (LVI) (P = 0.012) were independent factors associated with overall survival. In particular, CA 19-9 level and histologic type were determined to be independent factors affecting survival for more than 10 years. Conclusion CA 19-9 (≥38 U/mL), LN metastasis, and LVI were identified as independent risk factors for survival after resection of IHCC. CA 19-9 (<38 U/mL) and histologic type were independent factors predicting survival for more than 10 years.
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Affiliation(s)
- Chung Hyeun Ma
- Department of Surgery, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Dae Wook Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki Byung Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Song Cheol Kim
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang Hyun Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Hoon Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Song J, Chen W, Cui X, Huang Z, Wen D, Yang Y, Yu W, Cui L, Liu CY. CCBE1 promotes tumor lymphangiogenesis and is negatively regulated by TGFβ signaling in colorectal cancer. Am J Cancer Res 2020; 10:2327-2341. [PMID: 32089745 PMCID: PMC7019157 DOI: 10.7150/thno.39740] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022] Open
Abstract
Collagen and calcium-binding EGF domain-1 (CCBE1) is essential for lymphatic vascular development as it promotes vascular endothelial growth factor C (VEGFC) proteolysis. A recent study reported that CCBE1 was overexpressed in epithelial colorectal cancer (CRC) cells; however, the role of CCBE1 in tumor lymphangiogenesis and the mechanism underlying dysregulated CCBE1 expression in CRC remain undefined. Methods: The role of CCBE1 in tumor lymphangiogenesis and lymphatic metastasis was investigated using human lymphatic endothelial cells (HLECs) model in vitro, and a hindfoot lymphatic metastasis model in vivo. Immunochemistry analysis was performed to assess CCBE1 expression, prognostic value and correlation with clinicopathological characteristics in CRC. The biochemical function and transcriptional regulatory mechanism of CCBE1 were explored by western blot, qPCR, and chromatin immunoprecipitation. Results: Cancer cell-derived CCBE1 enhances VEGFC proteolysis in vitro, facilitates tube formation and migration of HLECs in vitro, and promotes tumor lymphangiogenesis and lymphatic metastasis in vivo. In addition to CRC cells, tumor stroma within CRC tissue shows high CCBE1 expression, which is associated with high lymphatic vessel density, increased lymph node metastasis and poor prognosis. Cancer-associated fibroblasts (CAFs) express and secret CCBE1, thereby contributing to VEGFC maturation and tumor lymphangiogenesis in CRC. Transforming growth factor beta (TGF-β) downregulates the transcription and lymphangiogenic function of CCBE1 in CAFs and CRC cells through direct binding of SMADs to CCBE1 gene locus. Inactivation of the TGF-β pathway correlates with increased CCBE1 expression in CRC. Conclusion: Our results demonstrate the protumorigenic role of CCBE1 in promoting lymphangiogenesis and lymphatic metastasis in CRC, revealing a new mechanism by which loss of TGF-β signaling promotes CRC metastasis.
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Shkurnikov MY, Maltseva DV, Knyazev EN, Alekseev BY. Expression of Stroma Components in the Lymph Nodes Affected by Prostate Cancer Metastases. Mol Biol 2018. [DOI: 10.1134/s0026893318050126] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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22
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Mochizuki T, Abe T, Amano H, Hanada K, Hattori M, Kobayashi T, Nakahara M, Ohdan H, Noriyuki T. Efficacy of the Gallbladder Cancer Predictive Risk Score Based on Pathological Findings: A Propensity Score-Matched Analysis. Ann Surg Oncol 2018; 25:1699-1708. [DOI: 10.1245/s10434-018-6444-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Indexed: 08/30/2023]
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23
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Light-sensitive dextran-covered PNBA nanoparticles as triggered drug delivery systems: Formulation, characteristics and cytotoxicity. J Colloid Interface Sci 2018; 514:289-298. [DOI: 10.1016/j.jcis.2017.12.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 12/27/2022]
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24
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Quantitative proteomics reveals that distant recurrence-associated protein R-Ras and Transgelin predict post-surgical survival in patients with Stage III colorectal cancer. Oncotarget 2018; 7:43868-43893. [PMID: 27270312 PMCID: PMC5190065 DOI: 10.18632/oncotarget.9701] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 05/08/2016] [Indexed: 12/14/2022] Open
Abstract
Surgical resection supplemented with adjuvant chemotherapy is the current preferred treatment for Stage III colorectal cancer (CRC). However, as many as 48% of patients who undergo curative resection eventually suffer from incurable distant recurrence. To investigate the molecular mechanisms involved in Stage III CRC post-surgical distant recurrence, we identified a total of 146 differentially expressed proteins (DEPs) associated with distant recurrence in Stage III CRC using TMT-based quantitative mass spectrometry. Among these DEPs, the altered expressions of R-Ras and Transgelin were then validated in 192 individual specimens using immunohistochemistry (IHC). Furthermore, Kaplan-Meier analysis revealed that the levels of R-Ras and Transgelin were significantly associated with 5-year overall survival (OS) and disease-free survival (DFS), and multivariate Cox-regression analyses revealed that R-Ras and Transgelin were independent prognostic factors for OS and DFS, respectively. In conclusion, this study identified potential biochemical players involved in distant recurrence and indicates that R-Ras and Transgelin are potential post-surgical prognostic biomarkers for Stage III CRC. This proteomics data have been submitted to Proteome Xchange under accession number PXD002903.
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25
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Bernier-Latmani J, Petrova TV. Intestinal lymphatic vasculature: structure, mechanisms and functions. Nat Rev Gastroenterol Hepatol 2017; 14:510-526. [PMID: 28655884 DOI: 10.1038/nrgastro.2017.79] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The mammalian intestine is richly supplied with lymphatic vasculature, which has functions ranging from maintenance of interstitial fluid balance to transport of antigens, antigen-presenting cells, dietary lipids and fat-soluble vitamins. In this Review, we provide in-depth information concerning the organization and structure of intestinal lymphatics, the current view of their developmental origins, as well as molecular mechanisms of intestinal lymphatic patterning and maintenance. We will also discuss physiological aspects of intestinal lymph flow regulation and the known and emerging roles of intestinal lymphatic vessels in human diseases, such as IBD, infection and cancer.
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Affiliation(s)
- Jeremiah Bernier-Latmani
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Institute of Pathology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (UNIL), Chemin des Boveresses 155, Epalinges, Switzerland
| | - Tatiana V Petrova
- Department of Fundamental Oncology, Ludwig Institute for Cancer Research and Institute of Pathology, Centre Hospitalier Universitaire Vaudois and University of Lausanne (UNIL), Chemin des Boveresses 155, Epalinges, Switzerland.,Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne, Route Cantonale 1015, Lausanne, Switzerland
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26
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Ethun CG, Postlewait LM, Le N, Pawlik TM, Buettner S, Poultsides G, Tran T, Idrees K, Isom CA, Fields RC, Jin LX, Weber SM, Salem A, Martin RCG, Scoggins C, Shen P, Mogal HD, Schmidt C, Beal E, Hatzaras I, Shenoy R, Merchant N, Cardona K, Maithel SK. A Novel Pathology-Based Preoperative Risk Score to Predict Locoregional Residual and Distant Disease and Survival for Incidental Gallbladder Cancer: A 10-Institution Study from the U.S. Extrahepatic Biliary Malignancy Consortium. Ann Surg Oncol 2017; 24:1343-1350. [PMID: 27812827 PMCID: PMC6054592 DOI: 10.1245/s10434-016-5637-x] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study was designed to develop a more robust predictive model, beyond T-stage alone, for incidental gallbladder cancer (IGBC) for discovering locoregional residual (LRD) and distant disease (DD) at reoperation, and estimating overall survival (OS). T-stage alone is currently used to guide treatment for incidental gallbladder cancer. Residual disease at re-resection is the most important factor in predicting outcomes. METHODS All patients with IGBC who underwent reoperation at 10 institutions from 2000 to 2015 were included. Routine pathology data from initial cholecystectomy was utilized to create the gallbladder cancer predictive risk score (GBRS). RESULTS Of 449 patients with gallbladder cancer, 262 (58 %) were incidentally discovered and underwent reoperation. Advanced T-stage, grade, and presence of lymphovascular (LVI) and perineural (PNI) invasion were all associated with increased rates of DD and LRD and decreased OS. Each pathologic characteristic was assigned a value (T1a: 0, T1b: 1, T2: 2, T3/4: 3; well-diff: 1, mod-diff: 2, poor-diff: 3; LVI-neg: 1, LVI-pos: 2; PNI-neg: 1, PNI-pos: 2), which added to a total GBRS score from 3 to 10. The scores were separated into three risk-groups (low: 3-4, intermediate: 5-7, high: 8-10). Each progressive GBRS group was associated with an increased incidence LRD and DD at the time of re-resection and reduced OS. CONCLUSIONS By accounting for subtle pathologic variations within each T-stage, this novel predictive risk-score better stratifies patients with incidentally discovered gallbladder cancer. Compared with T-stage alone, it more accurately identifies patients at risk for locoregional-residual and distant disease and predicts long-term survival as it redistributes T1b, T2, and T3 disease across separate risk-groups based on additional biologic features. This score may help to optimize treatment strategy for patients with incidentally discovered gallbladder cancer.
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Affiliation(s)
- Cecilia G. Ethun
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Lauren M. Postlewait
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Nina Le
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Timothy M. Pawlik
- Division of Surgical Oncology, Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD
| | - Stefan Buettner
- Division of Surgical Oncology, Department of Surgery, The Johns Hopkins Hospital, Baltimore, MD
| | - George Poultsides
- Department of Surgery, Stanford University Medical Center, Stanford, CA
| | - Thuy Tran
- Department of Surgery, Stanford University Medical Center, Stanford, CA
| | - Kamran Idrees
- Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Chelsea A. Isom
- Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Ryan C. Fields
- Department of Surgery, Washington University School of Medicine, St Louis, MO
| | - Linda X. Jin
- Department of Surgery, Washington University School of Medicine, St Louis, MO
| | - Sharon M. Weber
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Ahmed Salem
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Robert C. G. Martin
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, KY
| | - Charles Scoggins
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, KY
| | - Perry Shen
- Department of Surgery, Wake Forest University, Winston-Salem, NC
| | | | - Carl Schmidt
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Eliza Beal
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | - Rivfka Shenoy
- Department of Surgery, New York University, New York, NY
| | - Nipun Merchant
- Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN,Division of Surgical Oncology, Department of Surgery, University of Miami, Miami, FL
| | - Kenneth Cardona
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA
| | - Shishir K. Maithel
- Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, GA
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Lin J, Feng J, Jin Y, Yan Z, Lai Z, Peng J. Pien Tze Huang suppresses VEGF-C-mediated lymphangiogenesis in colorectal cancer. Oncol Rep 2016; 36:3568-3576. [PMID: 27779683 DOI: 10.3892/or.2016.5186] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/22/2016] [Indexed: 11/05/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies worldwide. The majority of patients are not suitable for surgery due to the presence of metastatic disease at the time of diagnosis, which has led to a high mortality rate for patients with CRC. Lymphangiogenesis, formation of new lymphatic vessels, plays an critical role in cancer progression particularly in cancer metastasis. Vascular endothelial growth factor-C (VEGF-C) has been previously demonstrated to play a pivotal role in cancer metastasis and therefore has become an attractive target for anticancer treatments. Pien Tze Huang (PZH) is a well-known traditional Chinese formula, which has exhibited significant therapeutic effects against CRC. However, the molecular mechanisms underlying its anticancer effects, particularly in regards to antimetastasis activity, still require further elucidation. In the present study, we evaluated the effects of PZH on cell migration and VEGF-C expression using various human CRC cell lines. Moreover, using a VEGF‑C-stimulated human lymphatic endothelial cell (HLEC) model, we demonstrated that PZH suppresses lymphangiogenesis by attenuating cell migration and tube formation. This indicates that PZH possesses significant antimetastatic activity. Moreover, suppression of lymphangiogenesis by PZH via the downregulation of VEGF-C may be a potential molecular mechanism by which PZH inhibits metastasis in CRC.
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Affiliation(s)
- Jiumao Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Jianyu Feng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Yiyi Jin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Zhaokun Yan
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Zijun Lai
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
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28
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Takatsuna M, Morohashi S, Yoshizawa T, Hirai H, Haga T, Ota R, Wu Y, Morohashi H, Hakamada K, Terai S, Kijima H. Myofibroblasts of the muscle layer stimulate the malignant potential of colorectal cancer. Oncol Rep 2016; 36:1251-7. [PMID: 27431808 PMCID: PMC4968616 DOI: 10.3892/or.2016.4932] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Accepted: 02/17/2016] [Indexed: 01/02/2023] Open
Abstract
Myofibroblasts of colorectal cancer (CRC) have been associated with histopathological factors such as lymph node metastasis, liver metastasis and local recurrence. However, few studies have assessed the association between these malignant potentials and the myofibroblast distribution in CRC. We aimed to evaluate the relationship between clinical factors and myofibroblast distribution around CRC invasive lesions. The study included 121 cases of pT3 CRC that were diagnosed at stage II or III. Myofibroblast density of the following three histological layers was measured: the submucosa (SM), muscularis propria (MP) and subserosa (SS). We analyzed the relationship between the clinicopathological factors and myofibroblast density by studying the histopathological features of the three layers. The myofibroblast density of the MP layer was significantly higher in the groups with high-frequency lymphatic and venous invasion than the groups with low-frequency lymphatic (P<0.001) and venous (P<0.01) invasion, respectively. In the positive lymph node metastasis group, the myofibroblast density at the MP layer was significantly higher than that in the negative lymph node metastasis group (P<0.001). The high myofibroblast density group at the MP layer was significantly associated with poor overall survival (P<0.003). Our study indicated that myofibroblasts are a type of cancer-associated fibroblasts and that the myofibroblast distribution contributes to the malignant potential of CRC. Furthermore, we demonstrated that myofibroblasts present at the MP layer play an important role in the malignant potential and poor prognosis of patients with CRC.
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Affiliation(s)
- Masafumi Takatsuna
- Department of Pathology and Bioscience
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan
| | | | | | | | | | - Rie Ota
- Department of Pathology and Bioscience
| | - Yunyan Wu
- Department of Pathology and Bioscience
| | - Hajime Morohashi
- Department of Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562
| | - Kenichi Hakamada
- Department of Surgery, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan
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29
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Tokodai K, Narimatsu H, Nishida A, Takaya K, Hara Y, Kawagishi N, Hashizume E, Ohuchi N. Risk factors for recurrence in stage II/III colorectal cancer patients treated with curative surgery: The impact of postoperative tumor markers and an infiltrative growth pattern. J Surg Oncol 2016; 114:368-74. [DOI: 10.1002/jso.24320] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/21/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Kazuaki Tokodai
- Department of Surgery; Nihonkai General Hospital; Japan
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
| | - Hiroto Narimatsu
- Cancer Prevention and Control Division; Kanagawa Cancer Center Research Institute; Japan
| | - Akiko Nishida
- Department of Pathology; Nihonkai General Hospital; Japan
| | - Kai Takaya
- Department of Surgery; Nihonkai General Hospital; Japan
| | - Yasuyuki Hara
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
| | - Naoki Kawagishi
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
| | | | - Noriaki Ohuchi
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
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30
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Gremonprez F, Willaert W, Ceelen W. Animal models of colorectal peritoneal metastasis. Pleura Peritoneum 2016; 1:23-43. [PMID: 30911606 DOI: 10.1515/pp-2016-0006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 03/04/2016] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer remains an important cause of mortality worldwide. The presence of peritoneal carcinomatosis (PC) causes significant symptoms and is notoriously difficult to treat. Therefore, informative preclinical research into the mechanisms and possible novel treatment options of colorectal PC is essential in order to improve the prognostic outlook in these patients. Several syngeneic and xenograft animal models of colorectal PC were established, studying a wide range of experimental procedures and substances. Regrettably, more sophisticated models such as those giving rise to spontaneous PC or involving genetically engineered mice are lacking. Here, we provide an overview of all reported colorectal PC animal models and briefly discuss their use, strengths, and limitations.
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Affiliation(s)
- Félix Gremonprez
- Department of Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium
| | - Wouter Willaert
- Department of Gastrointestinal Surgery, Ghent University Hospital, Ghent, Belgium
| | - Wim Ceelen
- Department of Gastrointestinal Surgery, Ghent University Hospital, 2K12 IC UZ Gent De Pintelaan 185, 9000 Ghent, Belgium
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31
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Kim N, Cho SB, Park YL, Park SY, Myung E, Kim SH, Yu HM, Son YA, Myung DS, Lee WS, Joo YE. Effect of Recepteur d'Origine Nantais expression on chemosensitivity and tumor cell behavior in colorectal cancer. Oncol Rep 2016; 35:3331-40. [PMID: 27035413 DOI: 10.3892/or.2016.4721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 12/03/2015] [Indexed: 11/05/2022] Open
Abstract
Recepteur d'Origine Nantais (RON) expression is known to induce oncogenic properties including tumor cell growth, survival, motility, angiogenesis and chemoresistance. In the present study, we evaluated whether RON affects chemosensitivity and oncogenic behavior of colorectal cancer cells and investigated its prognostic value in colorectal cancer. To evaluate the impact of RON on chemosensitivity and tumor cell behavior, we treated colorectal cancer cells with small interfering RNAs specific to RON. This was followed by flow cytometric analyses and migration, Matrigel invasion and endothelial tube formation assays. The expression of RON was investigated by immunohistochemistry in colorectal cancer tissues. TUNEL assay and immunohistochemical staining for CD34 and D2-40 were deployed to determine apoptosis, angiogenesis and lymphangiogenesis. RON knockdown enhanced 5-fluorouracil (FU)-induced apoptosis by upregulating the activities of caspases and expression of proapoptotic genes. Moreover, it enhanced 5-FU-induced cell cycle arrest by decreasing the expression of cyclins and cyclin‑dependent kinases and inducing that of p21. Furthermore, RON knockdown augmented the 5-FU-induced inhibition of invasion and migration of colorectal cancer cells. The β-catenin signaling cascade was blocked by RON knockdown upon 5-FU treatment. RON knockdown also decreased endothelial tube formation and expression of VEGF-A and HIF-1α and increased angiostatin expression. Furthermore, it inhibited lymphatic endothelial cell tube formation and the expression of VEGF-C and COX-2. RON expression was observed to be associated with age, tumor size, lymphovascular and perineural invasion, tumor stage, lymph node and distant metastasis, and poor survival rate. The mean microvessel density value of RON-positive tumors was significantly higher than that of RON-negative ones. These results indicate that RON is associated with tumor progression by inhibiting chemosensitivity and enhancing angiogenesis in colorectal cancer.
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Affiliation(s)
- Nuri Kim
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Sung-Bum Cho
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Young-Lan Park
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Sun-Young Park
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Eun Myung
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Seung-Hun Kim
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Hyung-Min Yu
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Young-Ae Son
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Dae-Seong Myung
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Wan-Sik Lee
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
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Krbal L, Hanušová V, Soukup J, John S, Matoušková P, Ryška A. Contribution of in vitro comparison of colorectal carcinoma cells from primary and metastatic lesions to elucidation of mechanisms of tumor progression and response to anticancer therapy. Tumour Biol 2016; 37:9565-78. [PMID: 26790446 DOI: 10.1007/s13277-016-4839-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 01/11/2016] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer has been a leading cause of cancer-related morbidity and mortality. For the research and individualization of therapy, primary cell lines of the colorectal cancer appear to be still an invaluable tool. We evaluated the differences in metastatic potential between four isolated primary colon cancer cells and cells derived from their lymph node metastasis. These results were compared with correspond immortalized cells-SW480 and SW620, respectively. The ability to migrate was tested using real-time measurement in xCELLigence system. Expressions of molecules involved in adhesion and invasion processes were examined using RT-PCR and western blot analysis. Furthermore, impact of cytotoxic effect of selected chemotherapeutics (irinotecan, oxaliplatin) and biological therapy (bevacizumab, cetuximab, panitumumab) was assessed by the WST assay. As expected, cell lines derived from lymph node migrated more aggressively and higher expression of adhesion molecules ICAM-1, EpCAM, and N-cadherin was detected. The expression of MMP-2 and -9 was elevated, on the other hand, in cell lines derived from primary tumor cancer cells as well as the expression of miR-21, miR-29a, and miR-200a. The most pronounced cytotoxic effect has been recorded with oxaliplatin and irinotecan (IC50 = 48.23 resp. 0.11 μg/ml), especially in cells originating from lymph node metastases. In total, comparison of isolated cell lines and immortalized cell lines has shown many similarities, as well as several differences. Adhesion/invasion molecules and several miRNAs, which play an important role in tumor development and the invasive and migratory behavior, could be a useful therapeutic target in malignant colorectal cancer.
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Affiliation(s)
- Lukáš Krbal
- The Fingerland Department of Pathology, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
| | - Veronika Hanušová
- Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, Hradec Králové, CZ-500 38, Czech Republic.
| | - Jiří Soukup
- The Fingerland Department of Pathology, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
| | - Stanislav John
- Department of Medical Biology and Genetics, Faculty of Medicine in Hradec Králové, Charles University in Prague, Šimkova 870, Hradec Králové, CZ-500 38, Czech Republic.,Department of Oncology and Radiotherapy, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
| | - Petra Matoušková
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, Hradec Králové, CZ-500 05, Czech Republic
| | - Aleš Ryška
- The Fingerland Department of Pathology, Faculty of Medicine and Faculty Hospital in Hradec Králové, Charles University in Prague, Sokolská 581, Hradec Kralove, CZ-500 05, Czech Republic
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Xue M, Lai SC, Xu ZP, Wang LJ. Noninvasive DNA methylation biomarkers in colorectal cancer: A systematic review. J Dig Dis 2015; 16:699-712. [PMID: 26565661 DOI: 10.1111/1751-2980.12299] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 10/25/2015] [Accepted: 11/08/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To summarize the current evidence on the biomarkers associated with DNA methylation in the screening and diagnosis of colorectal cancer (CRC). METHODS A literature search was conducted on the databases of PubMed and Web of Science to identify articles published from 1 January 2000 to 6 June 2015 with language striction. Stuides focusing on the association between noninvasive biomarkers indicating DNA methylation and CRC were included. RESULTS Altogether 74 studies were finally included in the study. Varied genetic markers in the feces and blood samples were hypermethylated in patients with CRC than in the healthy controls. Some of them could even be detected at the early stage of the tumors. The sensitivity of the genetic markers was superior to that of fecal occult blood test and carcinoembryonic antigen. Multitarget DNA assays using a combination of different methylated genes could improve the diagnostic sensitivity. CONCLUSIONS Genetic markers might be minimally invasive, economical and accurate for the screening and surveillance of CRC. Large multicenter studies evaluating these biomarkers systematically and prospectively not only in CRC but also in other types of cancers are needed in the future.
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Affiliation(s)
- Meng Xue
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
| | - San Chuan Lai
- Institute of Gastroenterology, Zhejiang University.,Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhi Peng Xu
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University
| | - Liang Jing Wang
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
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Lagarde SM, Phillips AW, Navidi M, Disep B, Immanuel A, Griffin SM. The presence of lymphovascular and perineural infiltration after neoadjuvant therapy and oesophagectomy identifies patients at high risk for recurrence. Br J Cancer 2015; 113:1427-33. [PMID: 26554656 PMCID: PMC4815887 DOI: 10.1038/bjc.2015.354] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 09/07/2015] [Accepted: 09/14/2015] [Indexed: 12/16/2022] Open
Abstract
Background: In patients treated for oesophageal cancer the importance of lymphovascular and perineural invasion (PNI) after neoadjuvant therapy has yet to be established. The aim of this study was to assess the incidence and prognostic significance of these factors in a consecutive series of patients with cancer of the oesophagus or gastro-oesophageal junction (GOJ) who underwent neoadjuvant therapy followed by oesophagectomy. Methods: Clinical and pathology results from patients with potentially curable adenocarcinoma, or squamous cell carcinoma of the oesophagus or GOJ were reviewed. Patients were treated with neoadjuvant chemotherapy or chemoradiation followed by transthoracic oesophagectomy and two-field lymphadenectomy. The presence of venous invasion (VI), lymph vessel invasion (LI) and perineural invasion (PNI) were correlated with clinical outcomes. Results: A total of 396 patients underwent oesophagectomy after neoadjuvant therapy for oesophageal cancer. Venous invasion was identified in 150 (38%) of patients, LI in 203 (51%) patients and PNI in 204 (52%) patients. In all, 123 (31%) patients had no evidence of either VI, LI or PNI. A total of 96 (24%) had a combination of two factors and 94 (24%) had all three factors. The presence of VI, LI and PNI was significantly related to tumour stage (P=0.001). Median overall survival was 170.8 months when all three factors were absent, 44.0 months when one factor was present, 27.1 months when two factors were present and 16.0 months when all were present. Multivariate analyses revealed VI, LI and PNI or a combination of these factors were independent predictors of prognosis. Conclusions: In oesophageal cancer patients treated with neoadjuvant therapy followed by oesophagectomy the presence of VI, LI and PNI has an important prognostic impact and may identify patients at high risk of recurrence who would benefit from adjuvant therapies.
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Affiliation(s)
- S M Lagarde
- Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-Upon-Tyne NE1 4LP, UK
| | - A W Phillips
- Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-Upon-Tyne NE1 4LP, UK
| | - M Navidi
- Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-Upon-Tyne NE1 4LP, UK
| | - B Disep
- Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-Upon-Tyne NE1 4LP, UK
| | - A Immanuel
- Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-Upon-Tyne NE1 4LP, UK
| | - S M Griffin
- Northern Oesophago-Gastric Cancer Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle-Upon-Tyne NE1 4LP, UK
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Abstract
The purpose of this study was to evaluate the presence of extracapsular invasion (ECI) in positive sentinel lymph nodes (SLNs) as a predictor of disease recurrence in breast cancer. SLN biopsy was performed on 318 breasts of 316 breast cancer patients, of which 50 (15.7%) had positive SLNs. Six (12.0%) of these 50 cases had disease recurrence. The clinicopathologic features of these cases were reviewed. The ECI at SLNs was not significantly associated with disease recurrence. The recurrence-free interval by Kaplan-Meier curves did not differ significantly among patients with and without ECI at SLNs. On the other hand, metastasis at non-SLNs was observed in 12 cases (24.0%) among the 50 cases with positive SLNs, and in the non-SLN metastasis group there were 7 patients with ECI at non-SLNs. Three of 7 cases with ECI at non-SLNs had disease recurrence and none of those 5 without ECI at non-SLNs had disease recurrence. Our current study suggests that the presence of ECI at metastatic SLNs is not associated with recurrent disease in breast cancer. Our results also imply that patients with ECI at positive non-SLNs have a high risk of disease recurrence.
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Oh HH, Park KJ, Kim N, Park SY, Park YL, Oak CY, Myung DS, Cho SB, Lee WS, Kim KK, Joo YE. Impact of KITENIN on tumor angiogenesis and lymphangiogenesis in colorectal cancer. Oncol Rep 2015; 35:253-60. [PMID: 26496979 DOI: 10.3892/or.2015.4337] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 09/18/2015] [Indexed: 11/06/2022] Open
Abstract
Angiogenesis and lymphangiogenesis are involved in the dissemination of tumor cells from solid tumors to regional lymph nodes and various distant sites. KAI1 COOH-terminal interacting tetraspanin (KITENIN) contributes to tumor progression and poor clinical outcomes in various cancers including colorectal cancer. The aim of the present study was to evaluate whether KITENIN affects tumor angiogenesis and lymphangiogenesis in colorectal cancer. A KITENIN small interfering RNA vector was used to silence KITENIN expression in colorectal cancer cell lines including DLD1 and SW480 cells. To evaluate the ability of KITENIN to induce angiogenesis and lymphangiogenesis in human umbilical vein endothelial cells (HUVECs) and lymphatic endothelial cells (HLECs), we performed Matrigel invasion and tube formation assays. Immunohistochemistry was used to determine the expression of KITENIN in colorectal cancer tissues. Angiogenesis and lymphangiogenesis were evaluated by immunostaining with CD34 and D2-40 antibodies. KITENIN silencing inhibited both HUVEC invasion and tube formation in the DLD1 and SW480 cells. KITENIN silencing led to decreased expression of the angiogenic inducers vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1α and increased expression of the angiogenic inhibitor angiostatin. KITENIN silencing did not inhibit either HLEC invasion or tube formation in all tested cells, but it resulted in decreased expression of the lymphangiogenic inducer VEGF-C. KITENIN expression was significantly associated with tumor stage, depth of invasion, lymph node and distant metastases and poor survival. The mean microvessel density was significantly higher in the KITENIN-positive tumors than that in the KITENIN-negative tumors. However, the mean lymphatic vessel density of KITENIN-positive tumors was not significantly higher than that of the KITENIN-negative tumors. These results suggest that KITENIN promotes tumor progression by enhancing angiogenesis in colorectal cancer.
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Affiliation(s)
- Hyung-Hoon Oh
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Kang-Jin Park
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Nuri Kim
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Sun-Young Park
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Young-Lan Park
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Chan-Young Oak
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Dae-Seong Myung
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Sung-Bum Cho
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Wan-Sik Lee
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Kyung-Keun Kim
- Department of Pharmacology, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Dong-ku, Gwangju 501-757, Republic of Korea
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Tacconi C, Correale C, Gandelli A, Spinelli A, Dejana E, D'Alessio S, Danese S. Vascular endothelial growth factor C disrupts the endothelial lymphatic barrier to promote colorectal cancer invasion. Gastroenterology 2015; 148:1438-51.e8. [PMID: 25754161 DOI: 10.1053/j.gastro.2015.03.005] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 02/25/2015] [Accepted: 03/02/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Colorectal cancer (CRC) is highly metastatic. Metastases spread directly into local tissue or invade distant organs via blood and lymphatic vessels, but the role of lymphangiogenesis in CRC progression has not been determined. Lymphangiogenesis is induced via vascular endothelial growth factor C (VEGFC) activation of its receptor, VEGFR3; high levels of VEGFC have been measured in colorectal tumors undergoing lymphangiogenesis and correlated with metastasis. We investigated VEGFC signaling and lymphatic barriers in human tumor tissues and mice with orthotopic colorectal tumors. METHODS We performed immunohistochemical, immunoblot, and real-time polymerase chain reaction analyses of colorectal tumor specimens collected from patients; healthy intestinal tissues collected during operations of patients without CRC were used as controls. CT26 CRC cells were injected into the distal posterior rectum of BALB/c-nude mice. Mice were given injections of an antibody against VEGFR3 or an adenovirus encoding human VEGFC before orthotopic tumors and metastases formed. Lymph node, lung, and liver tissues were collected and evaluated by flow cytometry. We measured expression of vascular endothelial cadherin (CDH5) on lymphatic vessels in mice and in human intestinal lymphatic endothelial cells. RESULTS Levels of podoplanin (a marker of lymphatic vessels), VEGFC, and VEGFR3 were increased in colorectal tumor tissues, compared with controls. Mice that expressed VEGFC from the adenoviral vector had increased lymphatic vessel density and more metastases in lymph nodes, lungs, and livers, compared with control mice. Anti-VEGFR3 antibody reduced numbers of lymphatic vessels in colons and prevented metastasis. Expression of VEGFC compromised the lymphatic endothelial barrier in mice and endothelial cells, reducing expression of CDH5, increasing permeability, and increasing trans-endothelial migration by CRC cells. Opposite effects were observed in mice and cells when VEGFR3 was blocked. CONCLUSIONS VEGFC signaling via VEGFR3 promotes lymphangiogenesis and metastasis by orthotopic colorectal tumors in mice and reduces lymphatic endothelial barrier integrity. Levels of VEGFC and markers of lymphatic vessels are increased in CRC tissues from patients, compared with healthy intestine. Strategies to block VEGFR3 might be developed to prevent CRC metastasis in patients.
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Affiliation(s)
- Carlotta Tacconi
- Humanitas Clinical and Research Center, IBD Center, Rozzano, Italy
| | - Carmen Correale
- Humanitas Clinical and Research Center, IBD Center, Rozzano, Italy
| | | | | | - Elisabetta Dejana
- FIRC Institute of Molecular Oncology Foundation (IFOM), Milan, Italy; Department of Biosciences, School of Sciences, University of Milan, Milan, Italy
| | - Silvia D'Alessio
- Humanitas Clinical and Research Center, IBD Center, Rozzano, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
| | - Silvio Danese
- Humanitas Clinical and Research Center, IBD Center, Rozzano, Italy.
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Fujii T, Yajima R, Morita H, Hirakata T, Miyamoto T, Fujisawa T, Tsutsumi S, Ynagita Y, Iijima M, Kuwano H. Impact of Vascular Invasion of a Primary Tumor as a Strong Risk Factor for Disease Recurrence in Patients with Node-Positive Breast Cancer. Am Surg 2015. [DOI: 10.1177/000313481508100537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The presence of lymph node metastasis is considered to be the most significant indicator of prognosis. However, in some cases with node-positive breast cancer, cancer cell dissemination is localized to the lymphatic systems. It is, therefore, important to develop selection criteria for strong adjuvant therapy in patients with node-positive breast cancer. This study was undertaken to evaluate the presence of vascular invasion that may reflect systemic disease as a predictor of disease recurrence in node-positive breast cancer. We retrospectively evaluated the cases of 134 consecutive female patients with breast cancer with lymph node metastasis who underwent radical breast operations. We examined the relationship between recurrence and clinicopathological factors, particularly vascular invasion. The presence of vascular invasion was found to be significant in a univariate analysis. The presence of vascular invasion was the independent risk factor in a multivariate analysis. Among the 66 patients without vascular invasion, four (6.1%) had disease recurrence. On the other hand, among the 68 patients with vascular invasion, 15 (22.1%) had a recurrence. It is interesting to note that despite the presence of lymph node metastasis, the group without vascular invasion had few patients with distant metastases. Our results suggest that the presence of vascular invasion could be an indicator of high biological aggressiveness and may be a strong prognostic factor for node-positive breast cancer.
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Affiliation(s)
- Takaaki Fujii
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Reina Yajima
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Hiroki Morita
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | | | | | | | - Soichi Tsutsumi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Yasuhiro Ynagita
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
| | - Misa Iijima
- Pathology, Gunma Prefectural Cancer Center, Ota, Gunma, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan and the Departments of
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Fragulidis GP, Vezakis A, Derpapas MK, Michalaki V, Tsagkas A, Polydorou AA. Cutaneous Metastatic Adenocarcinoma of the Colon to the Scalp. World J Oncol 2015; 6:304-307. [PMID: 29147421 PMCID: PMC5649951 DOI: 10.14740/wjon862w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2014] [Indexed: 11/11/2022] Open
Abstract
Cutaneous metastases from colorectal cancer are relatively uncommon presenting in fewer than 5% of patients but they are very important to recognize as they signify disseminated disease and poor prognosis. We describe a case a 62-year-old patient diagnosed with scalp metastasis during his systemic chemotherapy treatment for a colorectal carcinoma stage IVb who underwent excisional biopsy of the metastatic lesion. The identification of cutaneous metastases from colorectal cancer can radically alter therapeutic plans as they typically indicate a wide spread disease. Although they can be observed at any stage of malignancy, early recognition can lead to accurate and prompt diagnosis and timely treatment.
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Affiliation(s)
- Georgios P Fragulidis
- The 2nd Department of Surgery, Aretaieio Hospital, University of Athens Medical School, Greece
| | - Antonios Vezakis
- The 2nd Department of Surgery, Aretaieio Hospital, University of Athens Medical School, Greece
| | - Michael K Derpapas
- The 2nd Department of Surgery, Aretaieio Hospital, University of Athens Medical School, Greece
| | - Vassiliki Michalaki
- Department of Oncology, Aretaieio Hospital, University of Athens Medical School, Greece
| | - Athanassios Tsagkas
- Department of Pathology, Aretaieio Hospital, University of Athens Medical School, Greece
| | - Andreas A Polydorou
- The 2nd Department of Surgery, Aretaieio Hospital, University of Athens Medical School, Greece
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Yajima R, Fujii T, Yanagita Y, Fujisawa T, Miyamoto T, Hirakata T, Tsutsumi S, Iijima M, Kuwano H. Prognostic Value of Extracapsular Invasion of Axillary Lymph Nodes Combined with Peritumoral Vascular Invasion in Patients with Breast Cancer. Ann Surg Oncol 2014; 22:52-8. [DOI: 10.1245/s10434-014-3941-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Indexed: 12/30/2022]
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Chang CC, Lin BR, Wu TS, Jeng YM, Kuo ML. Input of microenvironmental regulation on colorectal cancer: Role of the CCN family. World J Gastroenterol 2014; 20:6826-6831. [PMID: 24944473 PMCID: PMC4051922 DOI: 10.3748/wjg.v20.i22.6826] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/25/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a major health problem causing significant morbidity and mortality. Previous results from various studies indicate that CRC tumorigenicity encompasses tumor microenvironment, emphasizing the complex interacting network between cancer cells and nearby host cells, which triggers diverse signaling pathways to promote the growth and spread of cancer cells. The CCN family proteins share a uniform modular structure, mediating a variety of physiological functions, including proliferation, apoptosis, migration, adhesion, differentiation, and survival. Furthermore, CCN proteins are also involved in CRC initiation and development. Many studies have shown that CCN members, such as CCN1, CCN2, CCN3, Wnt-induced secreted protein (WISP)-1, WISP-2, and WISP-3, are dysregulated in CRC, which implies potential diagnostic markers or therapeutic targets clinically. In this review, we summarize the research findings on the role of CCN family proteins in CRC initiation, development, and progression, highlighting their potential for diagnosis, prognosis, and therapeutic application.
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Caie PD, Turnbull AK, Farrington SM, Oniscu A, Harrison DJ. Quantification of tumour budding, lymphatic vessel density and invasion through image analysis in colorectal cancer. J Transl Med 2014; 12:156. [PMID: 24885583 PMCID: PMC4098951 DOI: 10.1186/1479-5876-12-156] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 05/26/2014] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Tumour budding (TB), lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) have shown promise as prognostic factors in colorectal cancer (CRC) but reproducibility using conventional histopathology is challenging. We demonstrate image analysis methodology to quantify the histopathological features which could permit standardisation across institutes and aid risk stratification of Dukes B patients. METHODS Multiplexed immunofluorescence of pan-cytokeratin, D2-40 and DAPI identified epithelium, lymphatic vessels and all nuclei respectively in tissue sections from 50 patients diagnosed with Dukes A (n = 13), Dukes B (n = 29) and Dukes C (n = 8) CRC. An image analysis algorithm was developed and performed, on digitised images of the CRC tissue sections, to quantify TB, LVD, and LVI at the invasive front. RESULTS TB (HR =5.7; 95% CI, 2.38-13.8), LVD (HR =5.1; 95% CI, 2.04-12.99) and LVI (HR =9.9; 95% CI, 3.57-27.98) were successfully quantified through image analysis and all were shown to be significantly associated with poor survival, in univariate analyses. LVI (HR =6.08; 95% CI, 1.17-31.41) is an independent prognostic factor within the study and was correlated to both TB (Pearson r =0.71, p <0.0003) and LVD (Pearson r =0.69, p <0.0003). CONCLUSION We demonstrate methodology through image analysis which can standardise the quantification of TB, LVD and LVI from a single tissue section while decreasing observer variability. We suggest this technology is capable of stratifying a high risk Dukes B CRC subpopulation and we show the three histopathological features to be of prognostic significance.
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Affiliation(s)
- Peter D Caie
- Digital Pathology Unit, Laboratory medicine, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.
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Bruun J, Kolberg M, Nesland JM, Svindland A, Nesbakken A, Lothe RA. Prognostic Significance of β-Catenin, E-Cadherin, and SOX9 in Colorectal Cancer: Results from a Large Population-Representative Series. Front Oncol 2014; 222:1-15. [PMID: 24904831 DOI: 10.1002/path.2727] [Citation(s) in RCA: 187] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Robust biomarkers that can precisely stratify patients according to treatment needs are in great demand. The literature is inconclusive for most reported prognostic markers for colorectal cancer (CRC). Hence, adequately reported studies in large representative series are necessary to determine their clinical potential. We investigated the prognostic value of three Wnt signaling-associated proteins, β-catenin, E-cadherin, and SOX9, in a population-representative single-hospital series of 1290 Norwegian CRC patients by performing immunohistochemical analyses of each marker using the tissue microarray technology. Loss of membranous or cytosolic β-catenin and loss of cytosolic E-cadherin protein expression were significantly associated with reduced 5-year survival in 903 patients who underwent major resection (722 evaluable tissue cores) independently of standard clinicopathological high-risk parameters. Pre-specified subgroup analyses demonstrated particular effect for stage IV patients for β-catenin membrane staining (P = 0.018; formal interaction test P = 0.025). Among those who underwent complete resection (714 patients, 568 evaluable), 5-year time-to-recurrence analyses were performed, and stage II patients with loss of cytosolic E-cadherin were identified as an independent high-risk subgroup (P = 0.020, formal interaction test was not significant). Nuclear β-catenin and SOX9 protein, regardless of intracellular location, were not associated with prognosis. In conclusion, the protein expression level of membranous or cytosolic β-catenin and E-cadherin predicts CRC patient subgroups with inferior prognosis.
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Affiliation(s)
- Jarle Bruun
- Department for Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital , Oslo , Norway ; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo , Oslo , Norway
| | - Matthias Kolberg
- Department for Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital , Oslo , Norway ; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo , Oslo , Norway
| | - Jahn M Nesland
- Department of Pathology, Oslo University Hospital , Oslo , Norway
| | - Aud Svindland
- Department of Pathology, Oslo University Hospital , Oslo , Norway ; Faculty of Medicine, University of Oslo , Oslo , Norway
| | - Arild Nesbakken
- Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo , Oslo , Norway ; Faculty of Medicine, University of Oslo , Oslo , Norway ; Department of Gastrointestinal Surgery, Aker Hospital, Oslo University Hospital , Oslo , Norway
| | - Ragnhild A Lothe
- Department for Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital , Oslo , Norway ; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo , Oslo , Norway ; Department of Molecular Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo , Oslo , Norway
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What could Nintedanib (BIBF 1120), a triple inhibitor of VEGFR, PDGFR, and FGFR, add to the current treatment options for patients with metastatic colorectal cancer? Crit Rev Oncol Hematol 2014; 92:83-106. [PMID: 24924525 DOI: 10.1016/j.critrevonc.2014.05.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 05/02/2014] [Indexed: 12/29/2022] Open
Abstract
Increasing knowledge of the pro-angiogenic processes involved in the progression of metastatic colorectal cancer (mCRC) has resulted in the clinical development of several anti-angiogenic agents, with bevacizumab currently being the only approved agent for mCRC. Nintedanib (BIBF 1120) has been shown to block the vascular endothelial growth factor receptor (VEGFR), the platelet-derived growth factor receptor (PDGFR), and the fibroblast growth factor receptor (FGFR). By targeting FGFR signaling, nintedanib may overcome resistance to previous anti-VEGF treatments, and may represent a better approach in patients with high basal levels of circulating FGFs. In this article, the angiogenic mechanisms implicated in mCRC are reviewed (focusing on the signaling pathways activated by VEGFR, PDGFR, and FGFR), along with the clinical data for nintedanib in the context of other anti-angiogenic tyrosine kinase inhibitors under clinical development for mCRC. Biomarkers that could predict response to nintedanib are also discussed.
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45
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Paschos KA, Majeed AW, Bird NC. Natural history of hepatic metastases from colorectal cancer - pathobiological pathways with clinical significance. World J Gastroenterol 2014; 20:3719-3737. [PMID: 24744570 PMCID: PMC3983432 DOI: 10.3748/wjg.v20.i14.3719] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/12/2013] [Accepted: 01/06/2014] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting.
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Abstract
Malignant tumors release growth factors such as VEGF-C to induce lymphatic vessel expansion (lymphangiogenesis) in primary tumors and in draining sentinel LNs, thereby promoting LN metastasis. Surprising recent evidence suggests that lymphatic vessels do not merely represent passive channels for tumor spread, but that they may actively promote tumor cell recruitment to LNs, cancer stem cell survival, and immune modulation. New imaging approaches allow the sensitive visualization of the earliest LN metastases and the quantitative, noninvasive measurement of the function of tumor-draining lymphatic vessels, with potential applications in the development of biomarkers for prognosis and measurement of therapeutic response.
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van Wyk HC, Roxburgh CS, Horgan PG, Foulis AF, McMillan DC. The detection and role of lymphatic and blood vessel invasion in predicting survival in patients with node negative operable primary colorectal cancer. Crit Rev Oncol Hematol 2013; 90:77-90. [PMID: 24332522 DOI: 10.1016/j.critrevonc.2013.11.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 10/09/2013] [Accepted: 11/14/2013] [Indexed: 12/15/2022] Open
Abstract
Although vascular invasion in colorectal cancer has been recognised since 1938, detection methods and results remain inconsistent. Vascular invasion is currently an independent prognostic factor in colorectal cancer influencing disease progression and survival. The vascular system consists of three components, arterial, venous and lymphatic vessels, all of which can be invaded but accurate distinction between the components remains difficult with routine staining techniques. Even though higher detection rates with elastica staining, for large vessel invasion, and recent techniques for immunohistochemistry for small vessel invasion, have been reported, a standardised method of detection has not been agreed upon which is reflected in the variability of published results. As a result of the Bowel Cancer Screening Programme in the UK it will be necessary to attempt to identify and stratify patients better, to be able to handle the stage migration to early node negative colorectal cancer. At present up to a third of patients, with node-negative colorectal cancer on conventional histopathological analysis, ultimately die of recurrent disease. It is therefore important to develop and standardised methods to identify lymphatic and blood vessel invasion which will influence ultimate survival. The present review summarises the current status of detection methods for these components of vascular invasion.
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Affiliation(s)
- Hester C van Wyk
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK.
| | - Campbell S Roxburgh
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - Paul G Horgan
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
| | - Alan F Foulis
- University Department of Pathology, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Southern General Hospital, Glasgow, UK
| | - Donald C McMillan
- Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, Glasgow, UK
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Lu Y, Zhuo C, Cui B, Liu Z, Zhou P, Lu Y, Wang B. TYMS serves as a prognostic indicator to predict the lymph node metastasis in Chinese patients with colorectal cancer. Clin Biochem 2013; 46:1478-1483. [PMID: 23810585 DOI: 10.1016/j.clinbiochem.2013.06.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 06/16/2013] [Accepted: 06/17/2013] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The current study is to evaluate the effect of thymidylate synthase (TYMS) on lymph node metastasis (LNM) in Chinese colorectal cancer (CRC) patients, and develop potential LNM-associated biomarkers for CRC. DESIGN AND METHODS Differences in TYMS gene expression between primary CRC with LNM (LNM CRC) and without LNM (non-LNM CRC) were assessed using quantitative real-time PCR analysis in 100 Chinese colorectal cancer patients. The relationship between clinicopathological parameters and prognosis of candidate biomarkers was also examined in the experiment. RESULTS TYMS was significantly upregulated in LNM CRC compared with non-LNM CRC, which was confirmed by real-time quantitative polymerase chain reaction. Overexpression of TYMS was significantly associated with LNM (P<0.001), advanced TNM stage (P<0.001), increased 5-year recurrence rate (P<0.001) and decreased 5-year overall survival rate (P<0.001). Univariate and multivariate analyses indicated that TYMS expression was an independent prognostic factor for recurrence and survival of CRC patients (P<0.05). CONCLUSIONS TYMS effect on lymph node metastasis in CRC might serve as a potential biomarker for LNM and a prognostic factor in CRC. Over-expression of TYMS is a predicting factor to the poor outcome in clinical colorectal cancer patients.
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Affiliation(s)
- Yuanfang Lu
- Department of Clinical Research Center, Affiliated 2nd Hospital of Nanjing Medical University, Jiang Jiayuan 121, Xiaguan District, Nanjing 210011, PR 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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Unal HU, Demiralay E, Tepeoğlu M, Fidan C, Kilickap S. Lack of relationships between FGF19 staining pattern, lymph node metastasis and locally invasive characteristics of the tumor in colorectal cancers. Asian Pac J Cancer Prev 2013; 14:3151-4. [PMID: 23803094 DOI: 10.7314/apjcp.2013.14.5.3151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION Colorectal cancers are in the top of the cancer-related causes of death in the world and lymph node metastasis is accepted as the primary prognostic factor. In this study, correlations of FGF19 staining pattern with local invasion and lymph node metastasis in a series of colorectal cancers were investigated. METHODS This studyincluded 81 colorectal cancer patients who underwent surgery in our hospital with no evidence of preoperative radiological distant metastasis. Routine pathological examination of the resection material was performed in order to identify vascular, perineural and serosal infiltration, regional lymph node metastasis and the degree of differentiation. Tumor tissue samples were stained with an immunohistochemistry method for FGF 19 evaluation and the staining pattern was statistically compared with the above mentioned characteristics of the tumors. RESULTS The patient population consisted of 47 females and 34 males with a median age of 70 years. In 40 patients regional lymph nodes were positive and 51%, 32% and 38% had serosal, perineural and vascular invasion. While 64 cases were moderately-differentiated, 11 cases were well-differentiated and 6 poorly- differentiated, there was no association with FGF 19 staining, including intensity. CONCLUSION No evidence of significant statistically correlation was found between FGF 19 staining pattern and serosal, perineural, vascular invasion, lymph node involvement and degree of differentiation.
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Affiliation(s)
- Hakan Umit Unal
- GastroenterologyDepartment, Baskent University Faculty of Medicine, Ankara, Turkey.
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