ONCOLOGY LETTERS 14: 3883-3892, 2017 Role of liver ICAM‑1 in metastasis (Review) AITOR BENEDICTO, IRENE ROMAYOR and BEATRIZ ARTETA Department of Cell Biology and Histology, School of Medicine and Nursing, University of The Basque Country, UPV/EHU, Leioa, E-48940 Vizcaya, Spain Received January 17, 2017; Accepted July 7, 2017 DOI: 10.3892/ol.2017.6700 Abstract. Intercellular adhesion molecule (ICAM)-1, is a frequently diagnosed cancer types and is the fourth leading transmembrane glycoprotein of the immunoglobulin (Ig)-like cause of cancer-related death (1). The spreading of cells from superfamily, consisting of five extracellular Ig‑like domains, a the primary lesion to a secondary organ and the subsequent transmembrane domain and a short cytoplasmic tail. ICAM-1 is development of distant metastases is a key factor that limits expressed in various cell types, including endothelial cells and patient survival rate. This remains one of the most complex leukocytes, and is involved in several physiological processes. issues faced in medicine (2). Furthermore, it has additionally been reported to be expressed The liver is the main target organ for metastatic CRC in various cancer cells, including melanoma, colorectal cancer cells and the second most commonly invaded organ, after and lymphoma. The majority of studies to date have focused the lymph nodes (3). In fact, 15-25% of CRC patients present on the expression of the ICAM‑1 on the surface of tumor cells, with synchronous hepatic metastases at the time of diagnosis, without research into ICAM‑1 expression at sites of metastasis. and a further 30% will later develop liver metastasis (4,5). Cancer cells frequently metastasize to the liver, due to its unique The complex network of vessels and microcapillaries of the physiology and specialized liver sinusoid capillary network. hepatic microcirculation makes the liver a target for circu- Liver sinusoidal endothelial cells constitutively express lating cells (6). Indeed, cancer cells released from a primary ICAM‑1, which is upregulated under inflammatory conditions. lesion follow a natural blood flow directly to the liver, through Furthermore, liver ICAM‑1 may be important during the devel- the specialized microvessel network known as the liver opment of liver metastasis. Therefore, it is necessary to improve sinusoids. Gastric cancers also commonly metastasize to the the understanding of the mechanisms mediated by this adhesion liver (7). Circulating cells from other primary malignancies, molecule in order to develop host‑directed anticancer therapies. such as melanoma, breast or neuroendocrine tumors (8-10), also adhere, establish and develop in the liver, giving rise to metastases, although this is less common. Contents Metastatic progression is a highly complex and coordi- nated cascade of events that is influenced by a wide variety 1. Introduction of mediators (11,12). Among the key factors that participate in 2. ICAM‑1 in healthy liver this process, adhesion molecules expressed on cancer cells and 3. ICAM‑1 in liver metastasis cells of the target organ have a crucial role (13,14). Adhesion 4. Conclusions molecules generate the initial cell-cell contacts that lead to cancer cell extravasation and organ colonization. Additionally, 1. Introduction these proteins may also act as signaling molecules to modulate the local microenvironment, creating a pro‑metastatic envi- Currently, cancer is one of most common causes of mortality ronment, and trigger an angiogenic and desmoplastic response worldwide. Colorectal cancer (CRC) represents one of the most via a complex reciprocal dialogue between the tumor cells and the cells of the colonized organ (15,16). In addition to the tissue cells, immune populations recruited from the circulation during metastasis formation are also involved in generating a favorable environment for metastatic growth (17,18). There- Correspondence to: Professor Beatriz Arteta, Department of Cell fore, determining the role of adhesion molecules during the Biology and Histology, School of Medicine and Nursing, University different stages of this process remains a major goal for our of The Basque Country, UPV/EHU, Barrio Sarriena, Leioa, E‑48940 understanding of the metastatic cascade. This, in turn, will Vizcaya, Spain E-mail: [email protected] facilitate new opportunities for therapeutic intervention. To date, the research effort undertaken to investigate Key words: liver metastasis, tumor microenvironment, adhesion the function of adhesion proteins expressed on the surface molecules, intercellular adhesion molecule‑1, invasion, immune of tumor cells and their implications in organ colonization response, angiogenesis has increased our knowledge about the signaling pathways that operate in tumor cells. The ‘seed and soil’ theory (19) postulates that host organ‑specific adhesion molecules are 3884 BENEDICTO et al: ROLE OF LIVER ICAM‑1 IN METASTASIS (REVIEW) required for the switch towards invasion and disease progres- cells initially require an anchor to adhere to and help them sion (20,21). Several adhesion molecules, such as E‑selectin, escape from the blood stream (Fig. 2). At this time, endothelial vascular cellular adhesion molecule (VCAM)‑1 and ICAM‑1, ICAM‑1 is involved in tumor cell adhesion to the endothelium; exhibit increased expression in the liver during metastatic this is a particularly important phenomenon considering that invasion (22). Among them, ICAM‑1 mediates several stages tumor adherence to vessel walls is a common feature across of the metastatic cascade, including the adhesion of tumor numerous types of cancer (51). Ghislin et al reported that cells to the endothelial wall (23-25), endothelial cell activa- ICAM‑1 expressed on the surface of endothelial cells is crucial tion of pro-metastatic signaling pathways (26-28), tumor for the adhesion of melanoma cells to the endothelial mono- cell extravasation (23,29), the recruitment of immune cell layer in vitro. Under these conditions, ICAM‑1 expression is populations (28,30,31), the pro-angiogenic response (32) and increased after tumor stimulation, in parallel with an increase the transdifferentiation of stellate cells during the desmo- in tumor cell adhesion, and this effect can be abrogated by the plastic response (33,34). This review will focus on the role of treatment of the endothelial cells with specific anti‑ICAM‑1 ICAM‑1 during the different events of the metastatic cascade antibodies (29). These results are consistent with another that drives colonization of the liver by circulating tumor cells, report that showed that tumor cell interaction with endothelial and how it modulates the liver microenvironment to facilitate cells increases ICAM‑1 expression on the endothelial cell metastasis. surface (52). Furthermore, expression of ICAM‑1 was shown to be correlated with the production of pro-tumoral cytokines, 2. ICAM‑1 in healthy liver such as IL-8 and IL-6. IL-8 and IL-6 facilitate tumor cell attach- ment to endothelial cells and enhance vascular permeability, ICAM-1 is a transmembrane glycoprotein of the immuno- as observed in models of brain and lung metastasis (53,54). globulin (Ig)‑like superfamily, consisting of five extracellular Additionally, a previous study used atomic‑force microscopy Ig-like domains, a transmembrane domain and a short cyto- to show that endothelial ICAM-1 mediates the adhesion of plasmic tail (35). This transmembrane domain is essential for different invasive bladder cancer cells to endothelial cells (24). cell‑cell adhesion and cell‑extracellular matrix (ECM) interac- In line with these results, a reduction in ICAM‑1 expression via tion (36,37). In the liver, ICAM‑1 is expressed constitutively in siRNAs or by using ICAM‑1‑blocking antibodies significantly liver sinusoidal endothelial cells (LSECs), hepatocytes, Kupffer decreased the adhesion of fibrosarcoma cells to ECV304 human cells (KCs) and hepatic stellate cells (HSCs) (33,38,39), and is endothelial cells in vitro (55), and of C26 CRC cells to LSECs and further upregulated by inflammatory activation, such as in vivo (56). Furthermore, the adhesion of different tumor cells stimulation by TNF-α, IL-1β or IFN-γ (40). As in other organs, may be reduced by blocking the expression of ICAM‑1 in the inflammation is accompanied by the recruitment of multiple endothelium of either brain or lung, leading to the abrogation immune cell populations, such as neutrophils, lymphocytes of metastasis to these organs, which further confirms the role and monocytes. Leukocytes invade the tissue after crossing of the ICAM-1 in tumor cells (53,54). Moreover, ICAM‑1 can the liver endothelium via interaction between endothelial cooperate with other adhesion molecules, such as VCAM‑1, ICAM-1 (41,42) and its main counter-receptor, lymphocyte in the adhesion of malignant cells. ICAM‑1 and VCAM‑1 function-associated antigen (LFA)-1, on lymphocytes. are both upregulated in a TNF-α-dependent manner (TNF-α being predominantly produced by macrophages) (57). Notably, 3. ICAM‑1 in liver metastasis LSECs lack the ability to express selectins, which are basally expressed and inducible in the endothelium of the portal ICAM‑1 appears to have a major role during the initiation tract and central vein (58). Likewise, this may have implica- of the metastatic cascade driving tumor progression. The tions for the pathophysiology of the liver and may affect expression of ICAM‑1 protein by liver parenchymal and the normal distribution of tumor cell adhesion during the non-parenchymal cells enhances its potential to facilitate first steps of infiltration. In parallel with the upregulation of disease progression (Fig. 1). In fact, ligand binding to ICAM-1 E‑selectin, ICAM‑1 and VCAM‑1 in the liver, the production in LSECs and KCs, and ICAM‑1 overexpression in HSCs of pro‑inflammatory cytokines is also increased in HCC (59). and hepatocytes (26,37,43,44) contribute to the activation of Among them, IL-6 is implicated in the attraction of tumor multiple signaling pathways with key roles in different stages cells, initiating a positive feedback response, and thus, not only of metastatic progression.