Mini-reviewCD146, a multi-functional molecule beyond adhesion
Highlights
► CD146 is a cell adhesion molecule (CAM) that is primarily expressed at the intercellular junction of endothelial cells. ► CD146 was originally identified as a marker for melanoma (MCAM). ► CD146 is not just a CAM for the inter-cellular and cell-matrix adhesion. ► CD146 is actively involved in miscellaneous processes, such as signaling transduction and angiogenesis. ► CD146 has been identified as a novel bio-marker for angiogenesis and for cancer.
Introduction
CD146 (cluster of differentiation 146) is a cell adhesion molecule (CAM) and belongs to the immunoglobulin superfamily (IgSF) [1]. CAMs are proteins located on the cell surface involved in the process of cell adhesion through the binding with other cells or with the extracellular matrix (ECM). Cell adhesion is a fundamental process required for the correct functioning of multicellular organisms. CAMs are involved in an extensive range of physiological processes, including cell–cell and cell-matrix interactions, cell migration, cell cycle, and signaling as well as morphogenesis during development and tissue regeneration. Increasing evidence highlights the fundamental role of CAMs in a variety of pathological progressions, such as cancer, inflammation, pathogenic infections, and autoimmune disease [2].
Johnson and colleagues are discoverers of CD146. In 1987, they reported that CD146 was expressed most strongly on metastatic lesions and advanced primary tumors and was only rarely detected in benign lesions [1]. CD146 is an integral membrane glycoprotein of 113 kDa, whose sequence of amino acids (AA) consists of a signal peptide, an extracellular fragment structure of V–V–C2–C2–C2 with five immunoglobulin-like domains, a transmembrane region and a short cytoplasmic tail [3], [4]. Subsequently, CD146 genome localization and organization, promoter structure [5], and the expression pattern in both human normal and malignant tissues [6] were reported by Johnson’s laboratory. Most interestingly, CD146 presents on the endothelia of blood vessels penetrating primary and metastatic melanomas, plays critical role in tumor angiogenesis and hematogenous spread, providing the first evidence for the mechanism underlying CD146-mediated tumor metastasis [7].
CD146 is a specific antigen in human malignant melanoma has also been confirmed simultaneously by another independent research group [8], [9]. Growing evidence has demonstrated that CD146 is overly expressed on a variety of carcinomas in addition to melanoma. Based on this attribute, CD146 attracts a plethora of attention, and therefore becomes an almost certain potential marker for tumor diagnosis, prognosis and treatment [7], [10], [11]. The majority of studies (50% more) about CD146 have focused on the observation of its role in varied processes of cancers, through down-regulation of CD146 expression via in vitro knockdown or in vivo inhibition in xenografted tumors in mice [11]. Over the past decades, precise details, especially concerning CD146 functions in various cancers, have been documented and further summarized in many reviews. Most of reports support the notion that CD146 promotes tumor growth, angiogenesis, and metastasis, and regard CD146 as a promising target for tumor therapy [4], [7], [10], [11], [12], [13], [14]. Therapeutic strategies targeting CD146 include humanized antibody [15], [16], [17] and vaccination [18], [19].
Contrast with the wide expression pattern of most other CAMs in normal tissues, the CD146 expression is restricted to limited adult normal tissues. However, its expression is broadly and highly detected in embryonic tissues. Recent investigations have revealed more multi-functional role for CD146, not merely limited to cell adhesion but expanded to processes such as development, signaling, cell migration and motility, proliferation, differentiation, and immune response. We will discuss the various newly identified functions of CD146 in physiological and pathological processes with the aim to update and present the knowledge about CD146.
Section snippets
The nomenclature of CD146
Human CD146 has been previously designated as different synonyms, including MUC18, A32 antigen, S-Endo-1, MCAM (melanoma CAM), Mel-CAM (melanoma CAM), MET-CAM (metastasis CAM) and HEMCAM (hemopoietic CAM), by several independent laboratories. Lehmann et al. originally discovered CD146 with a monoclonal antibody (mAb) of MUC18, which specifically reacted with human malignant cells but not with benign cells of melanocytic lineage, and thus designated this antigen as MUC18 [1], [3]. Coincidently,
The structure of CD146 gene
The exon–intron structure of CD146 genes from divergent examined species, i.e., human [5], mouse [27] and chicken [26], is similar. The full-length mRNA consists of 16 exons. The first exon of hCD146 (human CD146) encodes the 26-bp of 5′-UTR region and more than one-third of the signal leading peptide in the premature hCD146 polypeptide sequence. The first V (variable region) set and three C-2 (constant region) sets are each encoded by two exons. The second V set is encoded by three exons. The
CD146 protein
CD146 homologous proteins exibit high sequence identical among divergent species, including human [1], [3], mouse [30], [31], rat [32], [33], chicken [25], [26] and zebrafish [34]. The mature CD146 is composed of an extracellular fragment, a single trans-membrane region and a cytoplasmic tail [1], [3]. A structure of V–V–C2–C2–C2 Ig-like domain and 8 putative N-glycosylation sites are present in the extracellular fragment across species [26] (Fig. 2A). The premature CD146 has a signal peptide
CD146 expression regulation
How CD146 expression is regulated is highly pursued in the CD146 research area. It has been gradually clear that the manner of CD146 expression regulation is different in various tissues from embryo, tumor and adult. Based on the maximal sequence similarity between CD146 with an array of neural cell adhesion molecules expressed during organogenesis, CD146 was assumed to be regulated developmentally [3]. Although the regulation manner of CD146 expression during development still remains unknown,
CD146 and adhesion
CAMs are proteins located on the cell surface involved in the binding with other cells or with the extracellular matrix (ECM) in the process of cell adhesion. CAMs stick cells to each other and to their surroundings through interacting either with the same kind (homophilic binding) or with other CAMs, or the extracellular matrix (heterophilic binding). Four CAM families have been identified: the cadherins, the selectins, the integrins, and the immunoglobulin CAM superfamily (IgSF-CAM). CD146
CD146 and MSCs
MSCs defines a cell population of plastic-adherent multipotent mesenchymal stromal cells, comprising of a subset of cells with stem cell activity (i.e. the ability to undergo self-renewal or asymmetric cell division), which is also referred to as mesenchymal stem cells. Multipotent MSCs can differentiate into three cell types including: osteoblasts (bone cells), chondrocytes (cartilage cells), and adipocytes (fat cells). The umbilical cord MSCs have more primitive properties than other adult
CD146 and development
By comparing the abundance of CD146 between embryonic tissues and mature tissues, it has been found that high levels of CD146 are expressed in epithelia of nervous systems [56], trachea [76], kidney [77], [78] and oviduct [79] in embryonic tissues. After maturation, its protein levels decrease dramatically [80]. In addition, at the different stages of embryonic development, CD146 expression is variable. In early human embryos from 7 to 12 weeks of gestation, CD146 expression is higher compared
CD146 and immunology
Human CD146 is expressed by most elements of the microenvironment of normal human thymus, and is regarded as a pan-antigen with essential role for the maintenance of thymic architecture and function through mediating lymphocyte transmembrane migration and lymphocyte homing [92]. Human CD146 has been demonstrated to appear on a small subset of T [93] and B lymphocytes [94] in the peripheral blood of healthy individuals. By promoting the rolling on the inflammation marker VCAM-1 via microvilli
Signaling transduction by CD146
In addition to its role in cell–cell adhesion, CD146 participates in outside-in signaling in endothelial cells and is involved in the dynamics of actin cytoskeleton rearrangement. As shown in Fig. 3A, CD146 engagement initiates protein kinase phosphorylation cascade through association with Fyn, a Src family kinase. Phosphorylated Fyn in turn transfers phosphate to the downstream kinase of PKC-γ, which triggers Ca2+ burst within cells. Consequently, the induced association among proteins of
CD146 and angiogenesis
Angiogenesis is the physiological process relating the growth of new blood vessels from pre-existing vessels. Angiogenesis is a normal and fundamental process in growth and development, as well as in wound healing and in granulation tissue. However, it is also an essential step in the transition of tumors from a dormant state to a malignant one, leading to the use of angiogenesis inhibitors for cancer treatment. Although modern terms of angiogenesis differentiate into vasculogenesis,
CD146 and cancer
Sers et al. found that CD146 was highly expressed on advanced primary and metastatic melanomas but not on normal melanocyte, and that CD146 was associated with tumor progression and the development of metastasis in human malignant melanoma [5]. Subsequent investigations reveal that this protein was overly expressed in malignant and metastatic lesions [16], [120] in most of cancer types for promotion of tumor progression and metastasis as summarized in Table 1, Table 2. Contrary to this, scarce
CD146 as a target for cancer therapy
Over the past decades, “CD146 is an attractive target for cancer therapy” has been validated and documented by more than 50 investigations as summarized in Table 1, Table 2, and further summarized in many reviews [4], [7], [10], [11], [12], [13], [14]. Better understanding tumor growth and metastasis should obtain more insight on stromal microenvironment, such as the angiogenesis. Much research has been devoted to evaluating the reciprocal influences of angiogenesis with tumor development and
Concluding remarks
Increasing evidence demonstrates that CD146 is a multi-functional molecule implicated in a variety of biological and pathological processes. As a CAM, CD146 functions as a molecular mediator to facilitate inter-cellular interactions of homotypic or heterotypic cells, or to intervene in interactions of cell-to-extracellular matrix for responding to physiological signal. As a marker of endothelial cells in developmental vascular system and in tumor blood vessels, CD146 acts as a key player to be
Acknowledgements
We would like to thank our esteemed colleagues for carefully reading this manuscript and contributing to the progress of this work with their evaluation and insight. This work was partially sponsored by the National Natural Science Foundation China Grant 81272409, National Natural Science Foundation China Key Grant 91029732, and by Chinese State Key Programs for Basic Research (973) 2009CB521704.
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