Inflammation and breast cancer. Microenvironmental factors regulating macrophage function in breast tumours: hypoxia and angiopoietin-2

Abstract

Considerable evidence has now accumulated for tumour-associated macrophages stimulating key aspects of tumour progression, including the proliferation, survival and metastasis of tumour cells, tumour angiogenesis and suppression of the anti-tumour functions of other immune effectors at the tumour site. Tumour microenvironmental factors such as hypoxia have profound, direct effects on these cells, stimulating many of their pro-tumour functions. Hypoxia also does so indirectly by stimulating the release of the cytokine angiopoietin-2 from tumour cells and tumour blood vessels. This in turn then recruits Tie-2-expressing monocytes into tumours from the bloodstream and inhibits their production of anti-apoptotic and anti-angiogenic cytokines. Role of tumour-associated macrophages in tumour progressionTwo different approaches -the use of various transgenic mouse models and the analysis of human tumours -have demonstrated a close link between the activity of tumourassociated macrophages (TAMs) and tumour progression [1,2]. TAMs are abundant in most forms of solid tumour, where they often display a relatively immature phenotype and are positively correlated with tumour angiogenesis and/or progression (reviewed in [3]). Pollard's group crossed PyMT-MMTV mice (which spontaneously develop mammary tumours) with the transgenic op/op mouse model lacking the gene for colony-stimulating factor-1, a crucial growth factor for macrophages and their precursors from the bone marrow, namely blood monocytes. The tumours that developed in these macrophage-depleted mice showed a slower rate of progression to malignancy and formed far fewer metastases in the lungs than those in non-macrophage-depleted mice [1]. Moreover, Pollard's group recently characterised the development of the vasculature in PyMT-MMTV tumours during progression to malignancy and showed that the onset of the 'angiogenic switch' (the formation of the high-density vessel network associated with the transition to malignancy) was regulated by TAMs. Preinvasive mammary lesions in op/op mice exhibited both a delayed angiogenic switch and transition to malignancy, whereas genetic restoration of the macrophage population in tumours reversed this [4]. Although these studies suggest that TAMs have a key role in promoting tumour angiogenesis, progression to malignancy and metastasis, they have yet to be confirmed in similar studies with other macrophage-depleted, transgenic mouse tumour models.However, these data accord well with our finding that high numbers of TAMs correlate with increased tumour angiogenesis, lymph node status and reduced survival of breast cancer patients [5]. Moreover, we showed that TAMs in breast carcinomas express numerous tumour-promoting factors such as the important mitogen epidermal growth factor [6] and the pro-angiogenic cytokine vascular endothelial growth factor (VEGF) [7]. TAMs have also been shown to release a variety of other cytokines and enzymes known to promote tumour invasion, angiogenesis and metastasis [3,8]. Recent studies ind...

Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release

“…The critical role of the tumor microenvironment and -milieu on the differentiation process of blood monocytes into a tumor-associated macrophage phenotype in tumor tissues has also been studied in some detail (39,41,54,55). The chemotactic responsiveness of monocytes supposedly relates to a divergent expression of chemokines and chemokine receptors (56,57).…”

Tumor microenvironment and breast cancer progression

“…88 Studies on their function using different mouse models of breast cancer revealed that macrophages are required to regulate both the angiogenic switch and tumor progression and therefore play a key role in tumor development, invasion, and metastasis. 89,90 The tumor-promoting activities of TAM may result from their ability to express numerous tumor-promoting characteristics, such as growth factors for breast tumor cells, angiogenic mediators, ECM-degrading enzymes (MMPs), and inflammatory cytokines. For instance, monocyte-derived cytokines, such as TNF-a, may intensify chemokine expression by tumor or stroma cells besides possessing other promalignant properties.…”

Hormonal regulation of immune modulators in human breast tissue

“…Several studies have reported that approximately 50% of the breast tumor mass comprised of macrophages (81)(82)(83). Macrophages have also been implicated in promoting tumor initiation, progression, invasion, and metastases (84,85). Importantly, targeting tumor-associated macrophages using a vaccine-based approach has reduced tumor growth, tumor angiogenesis, and metastasis in many cancers, including breast cancer (86,87).…”