title: High macrophage infiltration along the tumor front correlates with improved survival in colon cancer.
abstract: OBJECTIVE
  The role of macrophages in tumorigenesis is complex because they can both prevent and promote tumor development.
  
  
  METHODS
  Four hundred forty-six colorectal cancer specimens were stained with the pan-monocyte/macrophage marker CD68, and average infiltration along the tumor front was semiquantitatively evaluated using a four-grade scale. Each section was similarly scored for the presence of CD68 hotspots. Some aspects of macrophage-tumor cell interactions were also studied using in vitro coculture systems.
  
  
  RESULTS
  Including all patients, regardless of surgical outcome and localization, survival increased incrementally with CD68TF(Mean) infiltration grade (P = 0.0001) but not in curatively resected colon cancers (P = 0.28). CD68 hotspot score (CD68TF(Hotspot)) was divided into high and low. A high hotspot score conferred a highly significant survival advantage also in curatively resected colon cancer cases (n = 199, P = 0.0002) but not in rectal cancers. CD68TF(Hotspot) high turned out as an independent prognostic marker for colon cancer in multivariate analyses including gender, age, localization, grade, stage, tumor type, and lymphocytes at the tumor front, conferring a relative risk of 0.49 (P = 0.007). In vitro coculture experiments, using phorbol 12-myristate 13-acetate-activated U937 cells as macrophage model, revealed that a high ratio of macrophages to colon cancer cells inhibited cancer cell growth. This was partially dependent on cell-to-cell contact, whereas Boyden chamber cocultivation without cell-to-cell contact promoted cancer cell spread.
  
  
  CONCLUSIONS
  In conclusion, our data indicate that a dense macrophage infiltration at the tumor front positively influences prognosis in colon cancer and that the degree of cell-to-cell contact may influence the balance between protumorigenic and antitumorigenic properties of macrophages.
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Forssell
authors.forename: Ake
authors.initials: A
authors.lastname: Oberg
authors.forename: Maria L
authors.initials: ML
authors.lastname: Henriksson
authors.forename: Roger
authors.initials: R
authors.lastname: Stenling
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.forename: Richard
authors.initials: R
authors.lastname: Palmqvist
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000401:mortality*; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000401:mortality*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C067980:CD68 antigen, human; D000097382:CD68 Molecule