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

Abstract

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 cellto-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.

Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages

“…[12][13][14] Some studies relying on immunohistochemical staining of human colorectal cancers, in fact, indicate that macrophages along the tumor margin [31][32][33] and macrophages expressing VEGF 34 are associated with a good prognosis. Others have suggested that macrophages in colorectal cancer may have co-stimulatory functions in antitumor immunity 35 or may be able to induce tumor cell apoptosis.…”

Effects of cytokine-induced macrophages on the response of tumor cells to banoxantrone (AQ4N)

“…Two studies on 26 and 30 patients, respectively, showed that low infiltration of macrophages correlated with more advanced colorectal cancer (45,46). A recent study indicated that a dense macrophage infiltration at the tumor front positively influenced prognosis in colon cancer (47). Hence, TAMs are an important feature of cancer and their level of infiltration into tumors has an important prognostic value.…”

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

“…The concept of cancer immune-surveillance has been supported by research showing that immune-deficiencies facilitate easy development of a neoplasm, further studies by animal models with inhibition of specific genes coding for the immune response resulted in a higher susceptibility to develop spontaneous or chemically-induced cancers (2,3). Previous studies showed that the infiltration of TAMs in colorectal cancer predicted a good prognosis (4)(5)(6)(7)(8). TAMs have been shown to be highly plastic cells that can display both tumor preventing (M1 macrophages) and tumor promoting functions (M2 macrophages) (9,10).…”