An Electron Microscope Study of Histiocyte Response to Ascites Tumor Homografts*

L. J. JOURNEYANDD. B. Aiviosf

(Experimental Biology Department, Roswell Park Memorial Institute, fÃujfaln.New York)

SUMMARY When the ascites forms of the DBA/2 lymphoma L1210 or the C57BL E.L. 4 lymphoma are injected into C3H mice, host histiocytes (macrophages) accumulate and are responsible for the destruction of a large number of tumor cells. Many of the tumor cells, often apparently intact, are ingested. The ingestion process is rapid and depends upon invagination of an area of the histiocyte with simultaneous projection of cytoplasmic fimbriae which complete the encirclement. The earliest change seen in the enclosed cell is shrinkage; digestion of the cell wall and cytoplasmic elements fol lows. Phagocytosis accounts for only a proportion of the cells destroyed by histiocytes. Other cells are probably destroyed when their cell membrane is broken down in an area in contact with a histiocyte, apparently permitting fusion of the two cytoplasms.

Weaver and his colleagues (13) observed that cytes and details some of the concomitant changes host cells were frequently found in close associa occurring in the histiocytes themselves. tion with tumor cells and described death of both host and incompatible tumor cell after a period of MATERIALS AND METHODS contact. Gorer (9) found that the predominant In a series of experiments 20 X IO7 cells from host cell in the ascites fluid during tumor rejection rapidly growing ascites populations of the lympho- was the histiocyte. This finding was confirmed, and mas E. L. 4 or L1210 native to C57BL and DBA/ some quantitative measurements were made by 2, respectively, were injected into the peritoneal one of us (1) and later by Weiser and his col cavity of young adult male C3H/He mice. In another series, 2 X IO6 C3H ascites sarcoma leagues (4). During rejection, both host and tumor cell have MClM cells were injected into C57BL male mice. increased susceptibility to damage by antibody The recipients were killed at daily intervals or by exogenous complement, and it appears that, from the 5th to the 10th day after inoculation, and in some instances, host histiocytes in the presence 0.2 ml. of the ascites fluid was withdrawn and of complement are damaged by antibody directed mixed immediately with 5 ml. of cold 2 per cent against the tumor (2). Light microscopy suggested osmic acid in 0.4 M sucrose. The viscous ascites that extremely close union occurs between tumor supernatant from the MClM tumor appeared to and host cell and that extracellular digestion is an give excellent protection to the cells during fixa alternative to phagocytic destruction as a means tion and subsequent embedding. of eliminating tumor cells from the population (3). After fixation, the cells were lightly centrifuged if gravity sedimentation had not occurred, the During the phase of acute rejection, host histio supernatant was removed, and the cells were cytes frequently appear to be degenerate, and dehydrated by the procedure described by Epstein there is an abrupt fall in their number. (6). This report describes some of the structural The fragments were embedded in prepolymerized changes accompanying the ingestion and later di methacrylate (95 per cent butyl + 5 per cent gestion of lymphoma or sarcoma cells by histio- methyl containing 1 per cent benzoyl peroxide) * Supported in part by U.S.P.H.S. Grant No. C-4461. and polymerization completed with L^.V. irradia t Present address: Duke University Medical Center, Dur tion. Sections were cut with glass knives, placed ham, N.C. on formvar-coated grids, and examined in an Received for publication May -2,196-3. RCA EMU 2B or 3F microscope. 998

RESULTS subjacent to the plasma membrane, suggesting The predominant C3H host cell type after in pinocytic activity. The cytoplasmic matrix was jection of L1210 lymphoma is the histiocyte. less dense than in tumor cells, because of the rela During late phases of the rejection of the tumor, tive absence of free ribosomes, and contained these cells may come to make up more than 75 per many ergastoplasmic tubules and small vesicles. cent of the ascitic population. Phagocytosis of Mitochondria appeared as short, dense rods, and tumor cells by histiocytes is extremely common, an extensive Golgi apparatus was usually seen be and, unlike the phagocytosis of A strain lympho tween the lobes of the nucleus (Figs. 5, 6). Granu ma #1 cells seen by Shelton and Dalton (10), lar bodies of varying sizes, termed round or residu leads to the rapid shrinkage and digestion of the al bodies by Palade and probably corresponding to ingested cells. From electron microscope prepara lysosomes, were another common feature of histio tions and Wright's stained smears, it appears that cyte cytoplasm. Inactive histiocytes had a few fat many intact tumor cells are being ingested. Tryp- droplets arranged in the peripheral cytoplasm, but an blue staining of fresh preparations indicated during periods of maximal reactivity contained nu that more than 92 per cent of the ascites popula merous irregular lipide particles of varying size tion was unstained and therefore presumably vi scattered throughout the cell. able. Phagocytosis.â€”Lymphoma cells were seen at Lymphoma cells.â€”The lymphoma cells were many different stages of ingestion. The earlier characterized by large, centrally placed nuclei sur steps must be very rapid, since very few cells are rounded by a thin rim of cytoplasm. In many in caught in this stage. Thin protoplasmic filaments stances the nuclei had deep indentions which gave project around the cell and rapidly envelop it in them a lobulated appearance. Chromatin material a film of cytoplasm. The ability to ingest other was disposed in patches near the nuclear envelope. cells is not confined to histiocytes; on rare occa Nucleolar material consisted of compact masses of sions a tumor cell is seen attempting phagocytosis. dense granules but occasionally assumed a loose, Although none of the tumor cells examined by filamentous arrangement. Mitochondria, which electron microscopy contained phagocytic vacu were few in number, were primarily of the round oles, very infrequently tumor cells containing or short rod variety, showing typical fine structure. phagocytized masses were encountered during Several large lipide droplets were commonly found light-microscope examination of smears, where the in each sectioned cell. The cytoplasm contained a sampling covered many thousands of lymphoma few isolated ergastoplasmic tubules but was filled cells. Extensive phagocytosis of dead histiocytes predominantly with free ribosome particles. Cyto- by A strain sarcoma cells has been noted by plasmic regions composed of fine fibrils were Gorer (9). found infrequently; no virus-like particles or in Ingestion of cell debris in cultured preparations clusions were encountered (Fig. 1). of HeLa cells occurs frequently. Numerous ex MClM ascites.-â€”The MC1M ascites cells were amples of phagocytized cell fragments in various rounded or oval, with large irregular nuclei, which stages of digestion have been seen during a study contained one to three prominent nucleoli. Mito of the fine structure of HeLa cells.1 Furthermore, chondria were large and pleomorphic with few histiocytes are capable of ingesting intact and pre cristae, resembling those previously described in sumably viable cells (10), whereas lymphoma cells the solid MClM tumor (5). Tubular elements of have been seen to ingest only debris or obviously the ergastoplasm were more numerous than in degenerate cells. lymphoma cells, but without evidence of inter Frequently two histiocytes will enclose a single connection. Scattered through the cytoplasm were tumor cell, although enclosure and digestion can lipide droplets and occasional fibrillar areas (Fig. proceed independently. The tumor cell seen in 2). The Golgi material consisted of stacked cis- Figure 7 is embedded in the cytoplasm of one of ternae with associated chains of microvesicles. the histiocytes, and fingerlike processes are ex Other cytoplasmic elements not commonly found tending along the surface. A second histiocyte is in ascites cells included granular bodies, possibly in close contact, but, while making no attempt to lysosomes, similar to those described in bladder enclose the tumor cell, is apparently starting to epithelia (12), and multivesicular bodies (Figs. 3, digest it. 4) of the type found in rat ova (11) and in human Digestion of lymphoma cells.â€”Phagocytosis is amnion cells (7). Histiocytes.â€”Typically, histiocytes possessed followed by rapid digestion. An analysis of the lobulated nuclei and had villi or protrusions along various changes following ingestion is shown in the cell periphery. Numerous vacuoles were found 1L. Journey and M. Goldstein, to be published.

Table 1. A typical course, based on an examination often contain a number of adequately fixed lym- of 70 ingested cells, would seem to be as follows: phoma cells in varying stages of digestion. The A distinct membrane lines a digestive vacuole mitochondria in less severely damaged histiocytes in about half the examples studied (Fig. 8). The often exhibit the same type of vesiculation seen in cell undergoing digestion shrinks progressively and the ingested cell. is often surrounded by a layer of fluid; sometimes Digestion usually involves a progressive loss of secondary vacuoles are seen nearby. The nucleus all cytoplasmic and nuclear structures of the lym- shows more advanced degenerative changes than phoma cell; but occasionally the remnants form the cytoplasm, and the nuclear membrane usually a dense, spongy osmiophilic mass, often internally disintegrates before the cytoplasmic membrane. vacuolated (Fig. 10). There is a suggestion from There is little correlation between the persistence two plates that this mass may be extruded (Fig. of a vacuolar and the cytoplasmic membrane, but 11); in other cases, small fragments appear to be in the more severely degraded inclusions the cell pinched off and may be seen in separate vacuoles. remnant appears to be in direct contact with the Phagocytosis and digestion of sarcoma MClM.â€” histiocyte cytoplasm. Mitochondria of the in Extensive phagocytosis of MC1M is rather less gested cell show vesicular changes in about one- common than phagocytosis of a lymphoma, but third of the examples examined. has been observed in some experiments. The tu-

TABLE 1 ANALYSISOFDEGENERATIVECHANGESIN70CELLS UNDERGOINGDIGESTIONIN38HISTIOCYTES

CELLTYPEIngested STUDIEDCytoplasm MEMBRANEPRESENT32 MITOCHON MEMBRANEPRE8FNT28 orslight4419VESICULARDRIA2411VACUOLAR

cellHistiocyteSTBUCTURE NucleusCytoplasmOUTER2038DEGENERATIONSevere354711Moderate31198None

The histiocytes themselves often show signs of mor cell is large relative to the histiocyte, and digestive breakdown, especially in the cytoplasm. simultaneous ingestion of more than one such cell The cause of this is unknown; it could be from an is rare. The sequence of changes appears to differ excess of activated enzymes released from the de from the digestion of lymphomas. generating ingested cell or could result from an A thin rim of cytoplasm surrounds the appar intracellular antigen-antibody reaction. Of 38 ently intact Sarcoma 1 cell (Fig. 12). The nucleus phagocytic histiocytes examined, nineteen showed begins to degenerate, but the nucleoli remain some evidence of loss of cytoplasmic detail. In clearly visible (Fig. 13). The cytoplasmic and eleven of these, the damage was marked, and in a nuclear membranes appear to remain intact, but few, most of the cytoplasmic structures including small vesicular bodies may be seen between the mitochondria, ergastoplasm, and Golgi have dis cytoplasmic membrane of the tumor cell and the appeared, the cell appearing remarkably empty vacuolar membrane of the histiocytes. These ap (Fig. 9). These changes are not fixation artifacts, pear to be budded off from the latter (Figs. 14, 15) since adjacent cells may show adequate fine struc but may be separated from it during subsequent tural details, and the severely affected histiocytes shrinkage of the ingested remnant. Degenerative

FIG. 1.â€”L1210tumor cell with large, dense nucleus. Several compact mitochondria and irregular lipide droplets are dis tributed in the cytoplasm. Other cytoplasmic elements include numerous microvesicles and free ribosomes, with no evidence of ergastoplasmic tubules. Stained with lead hydroxide. X 22,000.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. FIG. 2.â€”Part of an MC1M astiles cell showing the loosely arranged nucleolar granules. Mitochondria appear as large ovals with few eristae. Scattered through the cytoplasm are lipide droplets, many rough-surfaced ergastoplasmic tubules, and free ribosomes. XI 6,000.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Fio. 3.â€”Part of the cytoplasm of an MClM cell containing several inclusion bodies (arrows) within which arc found dense vesicles. X16,0(HI. FIG. 4.â€”Higher magnification of the multi-vesicular bodies revealing details of the enclosed heavy-walled vesicles. X 5-2,000.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Fio. 5.â€”Micrograph depicting structural components of a histiocyte before ingestion of tumor cell. Although the cell ap pears binucleate, it may represent the plane of section through a single, lolmlated nucleus (n). Lipide droplets are distributed in the peripheral cytoplasm. Typical Golgi elements are local ized between the nuclear lobes. Mitochondria and many ergastoplasmic elements are displaced throughout the cytoplasm. In one area (arrow) the histiocyte appears to be sending out villi to establish contact with a neighboring LH10 tumor cell.

PT;-.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. FIG. 6.â€”Higher magnification of a histioryte which includes part of the nucleus and details of mitochondria, stacked mem branes, and microvesicles of the Golgi and granular bodies (lysosomes?) of varying size. Stained with lead hydroxide. X16,000.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. FIG.7.â€”Micrograph of an LH10 tumor cell (T) sandwiched between two histiocytes (H-l and H-3). Histiocyte in upper part of picture has apparently established protoplasmic con tact, and the second has extended filamentous processes (ar rows) to engulf the tumor cell. Xuclei (n) of the histiocytes are indicated. X 1^,600.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Fio. 8.â€”Histiecytecontaining two ingested cells (/*â€¢-/ami pc-e). Tumor cell (Â¡Â«'-lÃ¬representsan early stage of assimila tion; the nucleus anil swollen mitochondria are still recogniz able. The other (Â¡>c-Â¿)representsa more advanced stage of di gestion in that the (â€¢ellremnantlias receded from the mem brane-bound vacuole, and there is marked vacuolization of the cytoplasm and dense nuclear material. Smaller phagocytic vacuoles (arrows) have pinched off and migrated into the sur rounding cytoplasm. The nucleus (n) and cytoplasmic elements of the histiocyte appear relatively normal. Xll.i-M). FIG.!).â€”Histiocvtecontaining the remnants of four phagocytized cells (pc). The histiocyte cytoplasm appears empty with a few lipide droplets and secondary phagocytic vacuoles but no mitochondria, indicating the impending disruption of the cell. X8.100.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Fio. 10.â€”Portion of a histiocyte in the LH10-C3H system containing two dense vacuolated masses whirl) probably repre sent the final stages of phagocytic digestion. XH,400. Flo. 11.â€”Micrograph showing portions of a histiocyte (//) and two E.L.4 tumor cells. The dense mass at center (arrow) appears as if it has just been expelled by the histiocyte. X 8,400.

% Â«â€¢-?*Â£ i K,r -'^-r -T- *jc-*S * * Â«Ã•----A i*,*>. >â€¢ ^ *- :V v \r i

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. FIG. li.â€”MCI M tumor cell immediately after ingestion by a liistiocyte. Note that the tumor cell is completely enclosed by the histiocyte and that its structures appear unaffected. X 10,000.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. FIG. 14.â€”Detailof the vesicles (arrows) that accumulate in the vacuolar space between the cytoplasmic membrane of the M( 'l M tumor cell (top) and the vacuolar membrane of the in gesting histiocyte (bottom). The vesicles appear to be budded off from the vacuolar membrane. XÃ¡Ã¡.Ã¼lM). FIG. 15.â€”Another example of vesicle accumulation (ar rows) at the boundary of the ingested tumor cell in a later stage of digestion. The cytoplasmic membrane and internal structures of the MCI M cell have been largely destroyed while the vesicles remain intact.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. FIG. 16.â€”Amore advanced stage in the digestion of two MClM cells in which few elements are still recognizable. X 9,000.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Fio. 17.â€”Histiocyteswith lar^e empty vacuoles from which the tumor cell contents were presumably resorbed were fre quently encountered in the MCI M in C57 system. Several smaller vacuoles containing dense osmiophilic material are also present. X9.000.

Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. FIG. 18.â€”Area of contact between a histiocyte and an MClM cell. There is interdif;itation of cytoplasmic processes of the two cells and vesicle formation and excessive infolding of the cell membrane of the histiocyte. There is no breach in the continuity of the cytoplasmic membranes. Xi'i.lKIO.

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Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1962 American Association for Cancer Research. Fio. 19.â€”Anexample in which villi of the histiocyte (if) have developÂ«!into open bridges (arrows) and continuity be tween the cytoplasms of histiocyte and tumor cell (7")has been established. Xii.OOO.

changes become extreme and lead to shrinkage small projection. There is an area (arrow) where and liquefaction of the ingested cell (Fig. 16). A the membrane is piled up, and numerous villi pro fluid-filled vesicle remains which probably col trude to meet an opposing lymphoma cell. Figures lapses, discharging the contents to the outside 18 and 19 show a similar process at a higher magni (Fig. 17). In contrast with the cytoplasmic degen fication. In the cells shown in Figure 19 there ap eration commonly seen following digestion of pears to be a definite breach in the wall of both lymphoma cells, the fine structure of the histio- cells. Degenerative changes are seen in the cyto cyte cytoplasm has remained intact during diges plasm of the tumor cell shown in Figure 19. tion of the sarcoma cells. Extracellular reactions.â€”Phagocytosis is not the REFERENCES only function of histiocytes. With some tumors 1. AMOS,D. B. Possible Relationships between the Cytotoxic such as the C3H sarcoma MC1M, phagocytosis is, Effects of Iso-antibody and Host Cell Function. Ann. N.Y. in fact, generally unusual, possibly because of the Acad. Sci., 87:273-90, 1960. large size of the tumor cells. Even with lympho- 2. . Host Response to Ascites Tumors. In: and Inter mas such as L1210 or E. L. 4 which are sensitive nat. Symp. Immunopathology, pp. 210-22. Basel: Benno Schwabe, 1962. to antibody and small enough to be readily en 3. . The Use of Simplified Systems as an Aid to the In gulfed, extracellular digestion appears to take terpretation of Mechanisms of Graft Rejection. In: place. Progress in Allergy, pp. 468-538. Basel and New York: Goldberg and Green found that heterospecific Karger, 1962. immune globulin would produce a spongelike tex 4. BAKER,P.; WEISEB,R. S.; JUTILA,J.; EVANS,C. A.; and BLANDAU,R.J. Mechanisms of Tumor Homograft Rejec ture of localized regions of the cytoplasmic mem tion. The Behaviour of Sarcoma I Ascites Tumors in the brane with a number of fimbrial processes which A/Jax and the C57BL/6K Mouse. Ann. N.Y. Acad. Sci. appeared to interdigitate with similar processes (in press). from other cells during agglutination (8). Similar 5. BERGSTRAND,A.,and RINQERTZ,N.Electron Microscopic Examination of the MClM Tumor. I. The Tumor in but less pronounced changes have been found on Ascites Form. J. Nat'l. Cancer Inst., 25:501-20, 1960. the cytoplasmic membranes of some host histio 6. EPSTEIN,M. A. The Fine Structure of the Cells in Mouse cytes in our preparations. In these mice, antibody Sarcoma 37 Ascitic Fluids. J. Biophys. & Biochem. Cytol., is being produced against the tumor; none would 3:567-76, 1957. be expected to be formed against the host. It has 7. FOGH,J., and EDWARDS,G.A. Ultrastructure of Primary Culture Amnion Cells and Transformed FL Cells in Con been suggested by one of us (3) that a local change tinuous Culture. J. Nat'l. Cancer Inst., 23:893-922, 1959. in the surface membrane of the host cell occurs fol 8. GOLDBERG,B.,and GREEN,H. The Cytotoxic Action of lowing contact with graft antigen. Increased per Immune Gamma Globulin and Complement on Krebs Ascites Tumor Cells. I. Ultrastructural Studies. J. Exp. meability from local degeneration of the cytoplas Med., 109:505-10, 1959. mic membrane would permit digestive enzymes to 9. GORER,P. A. Some Recent Work on Tumor Immunity. come into direct contact with tumor cells; progres Adv. Cancer Research, 4:149-86, 1956. sive digestion would then occur. 10. SHELTON,E., and DALTON,A. J. Electron Microscopy of Emperipolesis. J. Biophys. & Biochem. Cytol., 6:513-14, Considerably more evidence is needed before 1959. such a hypothesis can be accepted. Electron micro 11. SOTELO,J.R., and PORTER,K. R. An Electron Microscope graphs show a localized change of the type re Study of the Rat Ovum. J. Biophys. & Biochem. Cytol., 5:327-43, 1959. ported by Goldberg and Green (8) as being due to 12. WALKER,B. E. Electron Microscopic Observations on antibody in the area in contact with the target Transitional Epithelium of the Mouse Urinary Bladder. J. cell. Extracellular digestion was seen in a number Ultrastruc. Research, 3:345-61, 1960. of sections. 13. WEAVER,J. M.; ALGIRE,G. H.; and PREHN,R. T. The Growth of Cells in vivo in Diffusion Chambers. II. The Most of the surface of the histiocyte shown in Role of Cells in the Destruction of Homografts in Mice. J. Figure 5 is relatively smooth, with an occasional Nat'I. Cancer Inst., 15:1737-58, 1955.

L. J. Journey and D. B. Amos

Cancer Res 1962;22:998-1001.

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