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High Macrophage Infiltration along the Tumor Front Correlates with Improved Survival in Colon Cancer

Authors' Affiliations: ¹ Department of Medical Biosciences, Pathology, and ² Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden; and ³ Pathologisches Institut der Ludwig-Maximilians Universität, Munich, Germany

Requests for reprints: Richard Palmqvist, Department of Medical Biosciences, Pathology, Umeå University, SE-901 85 Umeå, Sweden. Phone: 46-90-785-1532; Fax: 46-90-785-2829; E-mail: richard.palmqvist{at}medbio.umu.se.

Purpose: The role of macrophages in tumorigenesis is complex because they can both prevent and promote tumor development.

Experimental Design: 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.