title: Close association between Fas ligand (FasL; CD95L)-positive tumor-associated macrophages and apoptotic cancer cells along invasive margin of colorectal carcinoma: a proposal on tumor-host interactions.
abstract: Anti-tumor immune responses are considered to be one of the key host reactions in human colorectal cancer, with T cells as important effector cells. For the induction of tumor-specific immunity, processing of cancer cells and priming of T cells by antigen-presenting cells are important. The present study was designed to clarify the relationship between Fas ligand (FasL; CD95L) expression and apoptotic cancer cells. Immunohistochemistry using frozen sections taken from 58 patients with colorectal cancer revealed that stromal cells composed mainly of tumor-associated macrophages expressed FasL, leaving cancer cells negative for FasL. These macrophages were abundantly distributed along the invasive margin. In situ hybridization revealed that these macrophages as well as cancer cells expressed FasL mRNA, whereas macrophages in the normal colon mucosa rarely expressed FasL. Apoptotic cancer cells recognized by monoclonal antibody M30 CytoDEATH were localized not only in cancer cell nests, but also in the stroma along the invasive margin showing a dissociated pattern, which was particularly evident in the areas of FasL+ macrophages. Furthermore, these macrophages, phenotypically similar to dendritic cells, occasionally contained M30+ apoptotic cancer cells in the cytoplasm. Clinicopathologic analyses in 123 cases revealed 1) a positive correlation between the degree of dissociated M30+ apoptotic cancer cells and the number of macrophages along the invasive margin and 2) an inverse association between the degree of dissociated M30+ apoptotic cancer cells and the occurrence of hematogenous metastasis after surgical resection of the primary tumor. In conclusion, the present study shows the importance of FasL+ activated macrophages as one of the host defense mechanisms against cancer cell spread in human colorectal cancer.
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan. hohtani@mito.hosp.go.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Sugita
authors.forename: Haruo
authors.initials: H
authors.lastname: Ohtani
authors.forename: Takayuki
authors.initials: T
authors.lastname: Mizoi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Saito
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shiiba
authors.forename: Iwao
authors.initials: I
authors.lastname: Sasaki
authors.forename: Seiki
authors.initials: S
authors.lastname: Matsuno
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyazawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagura
mesh_terms: D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D011379:Prognosis; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C505661:FASLG protein, human