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Activated leukocyte cell adhesion (ALCAM) is a member of the immunoglobulin superfamily and is a type of adhesion molecule that was first discovered in malignant melanoma. ALCAM is a transmembrane glycoprotein that is expressed at the junction between epithelial cells and is a member of the immunoglobulin superfamily and is involved in maintaining the stability of tissue structure. ALCAM consists of an intracellular region, a transmembrane region, an extracellular region consisting of five immunoglobulin domains, and a signal peptide consisting of a 27 amino acid amino-terminal hydrophobic. ALCAM exerts its pathophysiological function through the interaction of tropic (ALCAM-ALCAM) and heterophilic (ALCAM-CD6). Studies have shown that when ALCAM competes with the T cell surface antigen CD16, the homophilic effect of ALCAM is weaker than its heterophilic interaction with different cells.
Tudor et al. demonstrated that the binding of the Syntenin-1 protein to the cytoplasmic tail of ALCAM increased the stability and integrity of binding to ligand CD6. At present, a variety of miRNAs have been found to regulate the expression of ALCAM. Chen et al found that in breast cancer, miRNA-148a and miRNA-152 can directly act on the 3'UTR (non-coding region) of ALCAM to reduce the expression of ALCAM. In the MCF-7 cell line, Akman et al. found that miRNA-125b plays an indirect role in regulating ALCAM.
ALCAM is in the form of three forms of membrane ALCAM (mALCAM), cytoplasmic ALCAM (cALCAM) and soluble ALCAM (sALCAM). Although ALCAM mRNA can be detected in many tissues, the expression level and abnormal expression of ALCAM can cause changes in the pathophysiological process of the organism, which are closely related to the inflammatory reaction and the occurrence and development of the tumor. In different tumors, the expression subtypes and distribution regions of ALCAM are different, and the effects on tumor cells are also different. Xiao et al analyzed a variety of malignant solid tumors and concluded that ALCAM can be used as a candidate for cancer risk assessment, in which mALCAM is associated with lymph node metastasis of related tumors, and cALCAM is associated with TNM stage and disease-free survival (DFS). mALCAM, cALCAM, and sALCAM also have potential as biomarkers for predicting tumor survival in patients.
With the increasing research on ALCAM, it has been found that the occurrence, development, and metastasis of various cancers are closely related. ALCAM expression is different in different tumors, high expression in malignant salivary gland tumors and pancreatic cancer, and low expression in pediatric neuroblastoma. At the same time, ALCAM can also predict the sensitivity of tumors to drugs such as radiotherapy and chemotherapy and estrogen. The research on ALCAM has important significance for the diagnosis and treatment of tumors. However, the mechanism of action of ALCAM is still not clear, and more relevant research is still needed.
ALCAM and Gynecological Malignancies
Endometrial carcinoma (EC) is a group of malignant tumors that originate in the endometrium. EC is divided into estrogen-dependent (ECC, type I) and non-estrogen-dependent (UEEC, type II). The study found that ALCAM is closely related to the occurrence, development, and treatment of endometrial cancer. During the development of the normal endometrium into endometrial cancer, the expression of ALCAM and its mRNA is gradually increased. The level of ALCAM in cancer tissues was significantly higher than that in normal endometrial tissues, and its high expression was significantly associated with myometrial invasion. Patients with increased ALCAM have reduced tumor-free survival, and this difference is more pronounced in moderately poorly differentiated cancer. In the study, Devis et al found that the invasive and proliferative abilities of ALCAM-deficient endometrial carcinoma Hec1A and Ishikawa cell lines were significantly attenuated. Mice transfected with ALCAM-deficient endometrial cancer cell lines were observed to have a significantly reduced ability to metastasize, especially local metastasis, compared with the control group. They believe that ALCAM interferes with the ability of tumor cells to interact with the surrounding microenvironment.
Figure 1. Graphical scheme that illustrates the general structures and action principles for ALCAM, c-FLIP, and caveolin. (Lozneanu, et al. 2015).
Epithelial ovarian cancer (EOC) is the most common pathological type of ovarian cancer. The abnormal expression of ALCAM is associated with the invasion and metastasis of ovarian cancer and the sensitivity of patients to drugs. High expression of ALCAM is an independent risk factor for poor prognosis of ovarian cancer (OC). Studies have shown that ALCAM is normally expressed in the cell membrane in normal ovarian tissue and exists in the form of mALCAM. In the OC organization, it is mostly cALCAM, and the film positioning is degraded or disappeared. It is expressed almost exclusively in the form of cALCAM in ascites cancer cells. It is believed that the internalization of membrane ALCAM leads to a weakening of cancer cell adhesion and secondary abdominal metastasis. Carbotti et al. found that sALCAM was significantly higher in OC than normal ovarian tissue and positively correlated with CA125. This difference is more pronounced in type II ovarian tumors, even if stage I or stage II shows a significant increase in sALCAM. Therefore, it is considered that sALCAM elevation is an early feature of invasive EOC.
Some studies have analyzed ALCAM in cervical cancer tissues and serum, and immunohistochemical staining of cervical tissues in 233 patients, in which ALCAM is highly expressed in 58.4% of cervical cancer tissues. The experiment found that mALCAM was positively correlated with the expression of cALCAM. Although ALCAM is highly expressed in cervical cancer tissues, it has no significant correlation with clinical stage, pathological grade, tissue type and survival. In contrast, the expression level of ALCAM was inversely correlated with the expression of SCC-Ag in plasma.