Tumor-Associated Macrophage: Its Role in Cancer

Invasion and Metastasis

Jin-Yuan Shih, Ang Yuan1

, Jeremy J.-W. Chen, and Pan-Chyr Yang1

Department of Internal Medicine [J.-Y. Shih, P.-C. Yang] and Department of Emergency Medicine [A. Yuan], National

Taiwan University Hospital, Taipei, Taiwan; Center for Genomic Medicine, National Taiwan University College of

Medicine, Taipei, Taiwan [J. J.-W. Chen, P.-C. Yang]; Institutes of Biomedical Sciences and Molecular Biology,

National Chung-Hsing University, Taichung, Taiwan [J. J.-W. Chen]

Cancer metastasis is not exclusively regulated by the deregulation of metastasispromoting or suppressing genes in cancer cells. The interaction between cancer cells

and the stromal cells has been shown recently to promote cancer metastasis. The

macrophages within the tumor, referring to as tumour-associated macrophages

(TAMs), are the pivotal member of stromal cells. TAMs are derived from peripheral

blood monocytes recruited into the tumor. Upon activated by cancer cells, the TAMs

can release a vast diversity of growth factors, proteolytic enzymes, cytokines, and inflammatory mediators. Many of these factors are key agents in cancer metastasis.

The presence of extensive TAM infiltration has been shown to correlate with cancer

metastasis and poor prognosis in a variety of human carcinomas. TAMs promote cancer metastasis through several mechanisms including tumor angiogenesis, tumor

growth, and tumor cell migration and invasion. There are complex paracrine-signaling

networks between TAMs and cancer cells to activate each other. The colonystimulating factor 1/epidermal growth factor paracrine loop is well known in regulation

of breast cancer cells invasion. TAMs-derived proteases, such as matrix metalloproteinases, urokinase-type plasminogen activator, and cathepsin B can promote cancer

cells metastasis. The roles of TAMs in epidermal-mesenchymal transition of cancer

cells and resistance to cancer treatment are novel fields of study. On the other hand,

some investigations showed that the TAMs may play an important role in anti-tumor

activity. The control of TAMs to be pro-metastatic or tumoricidal is an important subject for cancer therapy.

Journal of Cancer Molecules 2(3): 101-106, 2006.




matrix metalloproteinase






Cancer progression is a complex multi-step process that

consists of transformation, tumor growth, invasion and metastasis. Tumor invasion and metastasis are the critical

steps in determining the aggressive phenotype of human

cancers, the obstacles to the successful treatment and major

causes of cancer deaths [1]. The spread of tumor cells from

a primary tumor to secondary sites within the body is a

complicated process involving the degradation of basement

membrane, invasion of stroma, adhesion, angiogenesis, cell

proliferation, migration, and anti-apoptosis [2]. Numerous

Received 6/12/06; Revised 6/14/06; Accepted 6/14/06. 1

Correspondence: Dr. Pan-Chyr Yang, Department of Internal Medicine, or Dr. Ang Yuan, Department of Emergency Medicine, National

Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei

100, Taiwan. Phone: 886-2-2356 2905. Fax: 886-2-2358 2867. E-mail:

pcyang@ha.mc.ntu.edu.tw (Pan-Chyr Yang) or navy@ha.mc.ntu.edu.tw

(Ang Yuan) 2

Abbreviations: ECM, extracellular matrix; TAMs, tumor-associated

macrophages; NSCLC, non-small cell lung cancer; CSF-1, colonystimulating factor 1; VEGF, vascular endothelial growth factor; MIF,

macrophage migration inhibition factor; PyMT, polyoma virus middle T

oncoprotein; TNF-α, tumor-necrosis factor-α; MMPs, matrix metalloproteinases; EGF, epidermal growth factor; EMT, epithelial–mesenchymal transition.

genetic changes and a variety of positive and negative factors may be involved in the molecular basis of metastasis [3].

During cancer progression, several rounds of mutation and

selection [4]