Forssell Johan, Oberg Ake, Henriksson Maria L, Stenling Roger, Jung Andreas, Palmqvist Richard
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
Clin Cancer Res. 2007 Mar 1;13(5):1472-9. doi: 10.1158/1078-0432.CCR-06-2073.
The role of macrophages in tumorigenesis is complex because they can both prevent and promote tumor development.
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.
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.
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.
巨噬细胞在肿瘤发生中的作用较为复杂，因为它们既能抑制肿瘤发展，也能促进肿瘤发展。
446例结直肠癌标本用全单核细胞/巨噬细胞标志物CD68染色，沿肿瘤前沿的平均浸润情况采用四级评分法进行半定量评估。对每个切片中CD68热点的存在情况进行类似评分。还使用体外共培养系统研究了巨噬细胞与肿瘤细胞相互作用的某些方面。
纳入所有患者，无论手术结果和肿瘤部位如何，CD68TF（平均）浸润分级越高，生存率越高（P = 0.0001），但在根治性切除的结肠癌中并非如此（P = 0.28）。CD68热点评分（CD68TF（热点））分为高和低。高热点评分在根治性切除的结肠癌病例中（n = 199，P = 0.0002）也具有显著的生存优势，但在直肠癌中并非如此。在包括性别、年龄、部位、分级、分期、肿瘤类型和肿瘤前沿淋巴细胞在内的多变量分析中，CD68TF（热点）高被证明是结肠癌的独立预后标志物，相对风险为0.49（P = 0.007）。体外共培养实验使用佛波醇12 - 肉豆蔻酸酯13 - 乙酸酯激活的U937细胞作为巨噬细胞模型，结果显示巨噬细胞与结肠癌细胞的高比例抑制癌细胞生长。这部分依赖于细胞间接触，而无细胞间接触的Boyden小室共培养促进癌细胞扩散。
总之，我们的数据表明肿瘤前沿密集的巨噬细胞浸润对结肠癌预后有积极影响，细胞间接触程度可能影响巨噬细胞促肿瘤和抗肿瘤特性之间的平衡。
