title: High-density lipoprotein of patients with breast cancer complicated with type 2 diabetes mellitus promotes cancer cells adhesion to vascular endothelium via ICAM-1 and VCAM-1 upregulation.
abstract: Adhesion of disseminating tumor cells to vascular endothelium is a pivotal starting point in the metastasis cascade. We have shown previously that diabetic high-density lipoprotein (HDL) has the capability of promoting breast cancer metastasis, and this report summarizes our more recent work studying the role of abnormal HDL in facilitating the adhesion of the circulating tumor cells to the endothelium. This is an initiating step in breast cancer metastasis, and this work assesses the role of ICAM-1 and VCAM-1 in this process. MDA-MB-231, MCF 7, and human umbilical vein endothelial cells (HUVECs) were treated with normal HDL from healthy controls (N-HDL), HDL from breast cancer patients (B-HDL), or HDL from breast cancer patients complicated with type 2 diabetes mellitus (BD-HDL), and the cell adhesion abilities were determined. ICAM-1 and VCAM-1 expression as well as the protein kinase C (PKC) activity were evaluated. The effect of PKC inhibitor and PKC siRNA on adhesion was also studied. The immunohistochemical staining of ICAM-1, VCAM-1, and E-selectin from breast cancer patients and breast cancer patients complicated with type 2 diabetes mellitus (T2DM) were examined. Our results indicate that BD-HDL promoted an increase in breast cancer cell adhesion to HUVECs and stimulated higher ICAM-1 and VCAM-1 expression on the cells surface of both breast cancer and HUVEC cells, along with the activation of PKC. Increased tumor cell (TC)-HUVEC adhesion, as well as ICAM-1 and VCAM-1 expression induced by BD-HDL, could be inhibited by staurosporine and PKC siRNA. In addition, a Db/db type 2 diabetes mouse model has more TC-Vascular Endothelium adhesion compared to a normal model. However, BD patients have a lower expression of ICAM-1, VCAM-1, and E-selectin in their tumor tissues. BD-HDL facilitates the adhesion of tumor cells to vascular endothelium by upregulating the expression of ICAM-1 and VCAM-1, thereby promoting the initial progression of breast cancer metastasis. This work indicates a prospective utilization of HDL-based strategies in the treatment of breast cancer patients with type 2 diabetes.
authors.affiliation: Department of Operating Room, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 40010, China.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Dan
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Operating Room, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 40010, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Ming
authors.affiliation: The Military General Hospital of Beijing, Beijing, 100700, China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: He
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Champion
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Auckland Bioengineering Institute, The University of Auckland, Auckland, 1142, New Zealand.
authors.forename: Hui
authors.initials: H
authors.lastname: Ren
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Nuclear Medicine, Institution of Radiation Medicine, Beijing Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Tianjin Key Laboratory of Radiation Medicine and Nuclear Medicine, Institution of Radiation Medicine, Beijing Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Military General Hospital of Beijing, Beijing, 100700, China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Jin
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ji
authors.affiliation: Proteomics Core Laboratory, Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China. panbintz@163.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Pan
authors.affiliation: The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University Health Science Center, Beijing, 100191, China. zhengl@bjmu.edu.cn.
authors.forename: Lemin
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000235:genetics* / Q000473:pathology; D019040:E-Selectin / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D008075:Lipoproteins, HDL / Q000097:blood / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D009362:Neoplasm Metastasis / Q000235:genetics; D009360:Neoplastic Cells, Circulating; D011493:Protein Kinase C / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D019040:E-Selectin; D008075:Lipoproteins, HDL; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D011493:Protein Kinase C
keywords: Breast cancer; Cell adhesion; HDL; ICAM-1; Type 2 diabetes mellitus; VCAM-1