Breast Tumor Angiogenesis and Tumor-Associated Macrophages: Histopathologist's Perspective

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Abstract

Much progress has been made since the conceptualization of tumor angiogenesis—the induction of growth of new blood vessels by tumor—as a salient feature of clinically significant primary or metastatic cancers. From a practicing histopathologist's point of view, we appraise the application of this concept in breast cancer with particular reference to the evaluation of proangiogenic factors and the assessment of new microvessels in histopathological examination. Recently, much focus has also been centered on the active roles played by tumor-associated macrophages in relation to tumor angiogenesis. We review the literature; many data supporting this facet of tumor angiogenesis were derived from the breast cancer models. We scrutinize the large body of clinical evidence exploring the link between the tumor-associated macrophages and breast tumor angiogenesis and discuss particularly the methodology and limitations of incorporating such an assessment in histopathological examination.

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Macrophages regulate the angiogenic switch in a mouse model of breast cancer.

Elaine Y Lin, Jiu-Feng Li, Leoid Gnatovskiy … (2006)

The development of a tumor vasculature or access to the host vasculature is a crucial step for the survival and metastasis of malignant tumors. Although therapeutic strategies attempting to inhibit this step during tumor development are being developed, the biological regulation of this process is still largely unknown. Using a transgenic mouse susceptible to mammary cancer, PyMT mice, we have characterized the development of the vasculature in mammary tumors during their progression to malignancy. We show that the onset of the angiogenic switch, identified as the formation of a high-density vessel network, is closely associated with the transition to malignancy. More importantly, both the angiogenic switch and the progression to malignancy are regulated by infiltrated macrophages in the primary mammary tumors. Inhibition of the macrophage infiltration into the tumor delayed the angiogenic switch and malignant transition whereas genetic restoration of the macrophage population specifically in these tumors rescued the vessel phenotype. Furthermore, premature induction of macrophage infiltration into premalignant lesions promoted an early onset of the angiogenic switch independent of tumor progression. Taken together, this study shows that tumor-associated macrophages play a key role in promoting tumor angiogenesis, an essential step in the tumor progression to malignancy.

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Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma.

R D Leek, C E Lewis, R. Whitehouse … (1996)

Angiogenesis is a key process in tumor growth and metastasis and is a major independent prognostic factor in breast cancer. A range of cytokines stimulate the tumor neovasculature, and tumor-associated macrophages have been shown recently to produce several important angiogenic factors. We have quantified macrophage infiltration using Chalkley count morphometry in a series of invasive breast carcinomas to investigate the relationship between tumor-associated macrophage infiltration and tumor angiogenesis, and prognosis. There was a significant positive correlation between high vascular grade and increased macrophage index (P = 0.03), and a strong relationship was observed between increased macrophage counts and reduced relapse-free survival (P = 0.006) and reduced overall survival (P = 0.004) as an independent prognostic variable. These data indicate a role for macrophages in angiogenesis and prognosis in breast cancer and that this cell type may represent an important target for immunoinhibitory therapy in breast cancer.

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Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues.

Craig Murdoch, Athina Giannoudis, Claire Lewis (2004)

The mechanisms responsible for recruiting monocytes from the bloodstream into solid tumors are now well characterized. However, recent evidence has shown that these cells then differentiate into macrophages and accumulate in large numbers in avascular and necrotic areas where they are exposed to hypoxia. This parallels their tendency to congregate in ischemic areas of other diseased tissues such as atherosclerotic plaques and arthritic joints. In tumors, macrophages appear to undergo marked phenotypic changes when exposed to hypoxia and to switch on their expression of a number of mitogenic and proangiogenic cytokines and enzymes. This then promotes tumor growth, angiogenesis, and metastasis. Here, we compare the various mechanisms responsible for monocyte recruitment into tumors with those regulating the accumulation of macrophages in hypoxic/necrotic areas. Because the latter are best characterized in human tumors, we focus mainly on these but also discuss their relevance to macrophage migration in ischemic areas of other diseased tissues. Finally, we discuss the relevance of these mechanisms to the development of novel cancer therapies, both in providing targets to reduce the proangiogenic contribution made by hypoxic macrophages in tumors and in developing the use of macrophages to deliver therapeutic gene constructs to hypoxic areas of diseased tissues.