Lin Elaine Y, Pollard Jeffrey W
Center for the Study of Reproductive Biology and Women's Health, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park, New York, NY 10461, USA.
Novartis Found Symp. 2004;256:158-68; discussion 168-72, 259-69.
In many solid tumour types the abundance of tumour associated macrophages (TAMs) is correlated with poor prognosis. Macrophages are recruited through the local expression of chemoattractants such as colony stimulating factor 1 (CSF-1) and macrophage chemoattractant protein 1. Over-expression of both of these factors is correlated with poor prognosis in a variety of tumours. Macrophages also play an important physiological role in the development and function of many tissues ranging from the brain to the mammary gland. Thus we hypothesized that TAMs are recruited to tumours through the expression of potent chemoattractants and in this site their normal trophic functions are subverted to promote tumour progression and metastasis. To test this hypothesis we crossed mice deficient in macrophages owing to being homozygous for a null mutation in the CSF-1 gene with mice pre-disposed to mammary cancer due to the epithelial restricted expression of the polyoma middle T oncoprotein. The absence of macrophages did not change the incidence or growth of the primary tumour but decreased its rate of progression and inhibited metastasis. These data are explicable through the known macrophage functions in matrix remodelling, angiogenesis and stimulation of tumour growth and motility through the synthesis of growth and chemotactic factors. Interestingly, these functions are also normally found in wound healing or pathologically during chronic inflammation. This supports the notion that tumours are 'wounds that never heal' and suggests that chronic inflammation through persistent infection or by other means might be an important cofactor in the genesis and promotion of tumours. Macrophages might therefore be important targets for cancer therapies.
在许多实体瘤类型中，肿瘤相关巨噬细胞（TAM）的数量与预后不良相关。巨噬细胞通过趋化因子如集落刺激因子1（CSF-1）和巨噬细胞趋化蛋白1的局部表达而被招募。这两种因子的过表达与多种肿瘤的预后不良相关。巨噬细胞在从脑到乳腺的许多组织的发育和功能中也发挥着重要的生理作用。因此，我们假设TAM通过强效趋化因子的表达被招募到肿瘤中，并且在这个部位它们正常的营养功能被颠覆，从而促进肿瘤进展和转移。为了验证这一假设，我们将由于CSF-1基因纯合无效突变而缺乏巨噬细胞的小鼠与由于多瘤病毒中间T癌蛋白的上皮限制性表达而易患乳腺癌的小鼠进行杂交。巨噬细胞的缺失并没有改变原发性肿瘤的发生率或生长，但降低了其进展速度并抑制了转移。这些数据可以通过已知的巨噬细胞在基质重塑、血管生成以及通过合成生长和趋化因子刺激肿瘤生长和迁移方面的功能来解释。有趣的是，这些功能在伤口愈合中也很常见，或者在慢性炎症的病理过程中也会出现。这支持了肿瘤是“永不愈合的伤口”这一观点，并表明通过持续感染或其他方式引起的慢性炎症可能是肿瘤发生和发展的一个重要辅助因素。因此，巨噬细胞可能是癌症治疗的重要靶点。
