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Potent Phagocytic Activity Discriminates Metastatic 0023-6837/03/8311-1555$03.00/0 LABORATORY INVESTIGATION Vol. 83, No. 11, p. 1555, 2003 Copyright © 2003 by The United States and Canadian Academy of Pathology, Inc. Printed in U.S.A. Potent Phagocytic Activity Discriminates Metastatic and Primary Human Malignant Melanomas: A Key Role of Ezrin Luana Lugini, Francesco Lozupone, Paola Matarrese, Cristina Funaro, Francesca Luciani, Walter Malorni, Licia Rivoltini, Chiara Castelli, Antonella Tinari, Adriano Piris, Giorgio Parmiani, and Stefano Fais Laboratories of Immunology (LL, FLo, CF, FLu, SF) and Ultrastructures (PM, WM, AT), Istituto Superiore di Sanità, Rome, and Unit of Immunotherapy of Human Tumors (LR, CC, AP, GP), Istituto Nazionale dei Tumori, Milan, Italy SUMMARY: Features of phagocytosis have been observed in human tumors, but the phagocytic apparatus of tumor cells and the mechanism(s) underlying this phenomenon have yet to be defined. To address the phenomenon of phagocytosis, its underlying mechanism(s), and its possible role in tumor biology, we used human melanoma cells as a prototypic model. Our results showed that a process of phagocytosis of apoptotic cells occurs in vivo in human melanoma. This finding was consistent with evidence that human melanoma cells in vitro express all of the known lysosomal and phagocytic markers on their cytoplasmic vesicles and that a process of phagocytosis occurs in these vesicles. However, exclusively human melanoma cells deriving from metastatic lesions possess an efficient phagocytic machinery responsible for a macrophage-like activity against latex beads, yeast, and apoptotic cells of different origins, which was comparable to that of human primary macrophages. Moreover, the actin-binding protein ezrin was expressed on phagocytic vacuoles of melanoma cells and of cells deriving from a human adenocarcinoma; both treatment with cytochalasin B and specific inhibition of ezrin synthesis strongly affected the phagocytic activity of melanoma cells. This suggests that the association with the actin cytoskeleton is a crucial requirement for the development of this phenomenon. Hence our data provide evidence for a potent phagocytic activity exerted by metastatic melanoma cells possibly involved in determining the level of aggressiveness of human melanoma. This suggests that the assessment of phagocytic activity may be exploited as a new tool to evaluate the malignancy of human melanoma. Moreover, our data suggest that gene therapy or drug treatments aimed at inhibiting actin assembly to the phagosomal membranes may be proposed as a new strategy for the control of tumor aggressiveness. (Lab Invest 2003, 83:1555–1567). he phagocytic-like behavior of tumor cells was cleus. However, signet-ring cells can also be found in T first observed a century ago (Steinhaus, 1891) nonepithelial tumors, such as malignant lymphomas and and confirmed by many other authors who described melanomas (Tsang et al, 1992). The nature of these cells, phagocytic activity of various murine and human tu- particularly in nonepithelial tumors, is not known, but it is mor cells against both dead cells and undefined conceivable that an aberrant scavenging activity under- particles (DeSimone et al, 1980; Marin-Padilla, 1977). lies this phenomenon (Banerjee and Harris, 2000; Ku- More recently, many morphologic aspects associated roda et al, 1999). Altogether these reports suggest that with phagocytosis have been identified in tumors active phagocytosis occurs in human tumor cells, but (Banerjee and Harris, 2000), and the phagocytic-like the phagocytic apparatus of tumor cells has never been activity of these cells has been associated with inva- defined and the mechanism(s) underlying this phenom- siveness (Coopman et al, 1998; Montcourrier et al, enon have not been investigated. 1994). Moreover, other histopathologic signs of tumor To address the phenomenon of phagocytosis, its malignancy, recalling an in vivo phagocytic-like be- underlying mechanism(s), and its possible role in tumor havior of tumor cells, have been described. Between aggressiveness, we used human melanoma cells as a the above mentioned signs there are the so-called prototypic model. In fact, it has been shown that mela- “signet-ring cells,” mostly typical of adenocarcinoma nosomes are specialized lysosomal-like organelles (Kuroda et al, 1999) and characterized by the pres- ence of intracytoplasmic mucin displacing the nu- (Dell’Angelica et al, 2000), able to fuse with phagosomes (Le Poole et al, 1993). This evidence is supported by the presence of an acidic pH, hydrolases, and acidic phos- DOI: 10.1097/01.LAB.0000098425.03006.42 phatases in these organelles, as well as by their expres- sion of some lysosomal-associated proteins (Lamp) Received April 8, 2003. (Dell’Angelica et al, 2000). Moreover, during melanogen- This work was supported by grants from AIRC (Associazione Italiana per la Ricerca sul Cancro), Milano, and from the Italian Ministry of Health, Rome. esis, melanoma cells (similar to professional phagocytes) Address reprint requests to: Dr. S. Fais, Laboratory of Immunology, Istituto increase their amount of tyrosinase-produced superox- Superiore di Sanita‘, 00161 Rome, Italy. E-mail: [email protected] ide anion (Koga et al, 1992). Laboratory Investigation • November 2003 • Volume 83 • Number 11 1555 Lugini et al Figure 1. In vivo autophagocytosis in melanoma tumors. A, Histologic preparation of a metastatic melanoma sample. A large epithelioid tumor cell contains an (apparently) intact tumor cell (arrow). The nuclear features of the “ingested” cell are the same as those present in the rest of the sample. [Hematoxylin and eosin (HE): magnification, ϫ350]. B, Histologic preparation of a metastatic melanoma sample. In the center of the field, a Tunel-positive (apoptotic) cell within a bigger, Tunel-negative cell is shown. (HE: magnification, ϫ350). Some recent data, obtained in murine macro- ficking (Tauton, 2001), both caused by an association phages, suggest a crucial role of the actin cytoskele- between cellular membranes and the actin cytoskele- ton in different phases of the phagocytosis process, ton through ERM (ezrin, radixin, and moesin). More- such as actin assembly on secondary phagosome over, we have recently shown that the bacterial-toxin– membranes (Defacque et al, 2000) and vesicular traf- induced activation of some actin-regulatory proteins Figure 2. Expression and distribution of phagocytic markers in melanoma cells. Lysosomal-associated protein-1 (Lamp-1) (A), Rab7 (B), and CD68 (C) stainingsina representative melanoma cell line. The inset in A shows an electronic magnification (ϫ3500) of the area indicated by the arrowhead (bar ϭ 0.5 ␮m). Immunophenotyping of fixed cells was performed using the peroxidase anti-peroxidase (PAP) method. AEC was used as chromogen and Mayer’s hematoxylin for the counterstaining. Final magnification, ϫ1500. (D) Western blot analysis of Rab5, Rab7, Lamp-1, and Lamp-2 proteins on total protein extract of four (1, 2, 3, 4) melanomas as compared with human primary macrophages (m). The relative molecular weights are indicated. 1556 Laboratory Investigation • November 2003 • Volume 83 • Number 11 Phagocytic Activity of Metastatic Melanoma (ie, ␳-GTPase) results in the induction of a genuine confirmed the expression of the phagocytic markers phagocytic activity in a human epithelial cell line by melanoma cells and showed comparable molecular (Fiorentini et al, 2001), further suggesting a crucial role weights of these proteins between melanoma cells of the actin cytoskeleton in this process. and professional phagocytes (Fig. 2D). Figure 3 (A to On the basis of these considerations, the goals of D) shows additional findings suggesting a possible this study were as follows: (i) to evaluate the in vivo phagocytic sequence of the ingested autologous cells occurrence of phagocytosis in human melanoma; (ii) (early contact and internalization: Figure 3, A and B; to assess the presence of phagocytosis in human and total degradation: Fig. 3, C and D), occurring in melanoma cells and characterize the phagocytic ma- vacuoles stained for a phagocytic marker (ie, CD68). chinery of melanoma cells and its possible relationship These results clearly show that the phagocytic mark- with the phagocytic activity; (iii) to evaluate both the ers were mostly localized on vacuoles containing cells ability of melanoma cells to ingest and phagocyte in various stages of degradation, suggesting the oc- amorphic material (latex beads), yeasts, and dead currence of a genuine phagocytosis in human mela- cells and the relationships between phagocytic activ- noma cell cultures. Moreover, these data definitively ity and the malignancy of melanoma; and (iv) to demonstrate that a genuine macrophage-like phago- understand the key mechanism(s) underlying this cytic behavior underlies the frequent in vivo findings of phagocytic activity. Our results showed that human autophagocytic figures in histopathologic specimens melanoma cells deriving from metastatic lesions, but of human melanoma (Banerjee and Harris, 2000). not from primary tumors, possess an efficient phago- cytic machinery responsible for a macrophage-like In Vitro Phagocytic Activity of Human Melanoma Cells activity against latex beads, yeast, and apoptotic cells and that ezrin holds a key role in the phagocytic To assess the phagocytic activity of human melanoma activity of metastatic melanoma cells. cells, we measured the ability of 8 primary and 11 metastatic human melanoma cell lines to ingest either Results latex beads or apoptotic
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