Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland

Ingman, Wendy V.; Wyckoff, Jeff; Gouon-Evans, Valérie; Condeelis, John S.; Pollard, Jeffrey W.

doi:10.1002/dvdy.20972

Cited by 247 publications

(228 citation statements)

References 20 publications

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“…Many of these fibres are tethered to blood vessels, resulting in cancer cells accumulating at these vessels 55 . The density of these fibres is regulated by macrophages, at least during development 56 .…”

Section: Tumour-associated Macrophagesmentioning

confidence: 99%

Microenvironmental regulation of metastasis

2008

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Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves ratelimiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.A variety of stromal cells in the surrounding environment are recruited to tumours, and these not only enhance growth of the primary cancer but also facilitate its metastatic dissemination to distant organs. Cancer cells in an aggressive primary mass are adept at exploiting that particular tissue microenvironment; however, once they leave these favourable surroundings, they must possess traits that will allow them to survive in new environments. In order for a metastasis to occur, the intravasated cancer cell must survive in the circulation, arrive at the target organ (seeding), extravasate into the parenchyma and show persistent growth 1 . Each of these stages is inefficient and some are rate limiting 1,2 . For example, senescence or apoptosis of cancer cells at the stage of entry into the metastatic site prevents the spread of the majority of circulating cells [2][3][4] . Seeding can occur to multiple organs, but metastatic tumours may grow in only one or a few 5 . There is also increasing evidence that in some cases cancer cells can lie dormant for many years, and that seeding may occur several years before diagnosis of the primary tumour [6][7][8][9][10] . In another phenomenon, termed angiogenic dormancy, there is a balance of proliferation and apoptosis that results in micrometastases that do not progress further 11,12 . The microenvironment clearly suppresses NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the malignancy of these potentially metastatic cells 10 , and their re-activation to form a clinically relevant metastasis probably occurs through perturbations in the microenvironment. Nevertheless, despite this evidence for early seeding and dormancy, tumour size and grade are the main predictors of metastasis, and this has been reinforced in recent studies in mouse models 13 and by gene expression analysis that linked large tumour size with metastasis-enhancing gene signatures 14 . It has been hypothesized that this may be due to metastatic re-seeding to primary tumours 15 . If this is the case, nothing is currently known about the underlying mechanisms. Successful metastatic outgrowth thus depends on the cumulative ability of cancer cells to appropriate distinct microenvironments at each step in the metastatic cascade: the primary tumour, systemic circulation and the final metastatic site. In this Review we discuss instruct...

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Section: Tumour-associated Macrophagesmentioning

confidence: 99%

Microenvironmental regulation of metastasis

2008

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“…In mammary tumours in particular, macrophages provide signals to tumour cells for chemotaxis and cell motility that lead to invasion and metastasis. In this context macrophages help provide the microenvironment for metastasis in a similar way to the function of macrophages during normal mammary morphogenesis 89 . This suggests that metastasis may be an unregulated repetition of morphogenesis 15 .…”

Section: Future Directionsmentioning

confidence: 99%

The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

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Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.Tumour cell motility is the hallmark of invasion and an essential step in metastasis 1,2 . The identification of molecular pathways that contribute to tumour cell motility and invasion is essential for understanding how motility is initiated in tumour cells and how the tumour microenvironment contributes to cell migration. The identification of the molecular pathways of tumour cell invasion will provide new diagnostic approaches and targets for the treatment of metastatic cancer. Recent studies using new technologies, including highdensity microarray-based expression profiling, intravital imaging and the collection of invasive tumour cells from live tumours, have started to extend the traditional model of metastasis and supply new diagnostic and therapeutic markers of metastatic disease.According to the traditional model of metastasis, metastases result from a process similar to Darwinian evolution whereby natural selection works on individual tumour cells to select © 2007 Nature Publishing Group Correspondence to: J.C. Condeeli@aecom.yu.edu. Competing interests statementThe authors declare no competing financial interests. for stable genetic changes. The cells so selected are very rare, and the metastatic cells that arise from this progressive selection of stable genetic mutations within the primary tumour cause metastasis late in tumour progression 3 . However, studies of mammary tumours in mice [4][5][6][7] , expression profiling of both whole human breast tumours 8,9 and the invasive subpopulation of tumour cells isolated from rat and mouse mammary tumours [10][11][12] suggest that the metastatic ability of breast tumours is encoded throughout the bulk of the primary tumour, involves transient changes in gene expression and is acquired at much earlier stages of tumour progression than postulated by the traditional model. These results suggest that a Darwinian-like evolution is accompanied by, and may contribute to, microenvironmentinduced transient changes in gene expression that support the invasive and metastatic phenotype. These results have led to new models where the microenvironment initiates the expression of genes that induce cell motility, invasion and metastasis 11,13 . In the 'tumour microenvironment invasion model' it is proposed that oncogenic mutations in tumour cells lead to microenvironments that are potentially encoded throughout the b...

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“…The tubular structure with the visible collagen sheaf running laterally across the image in B is a blood vessel. In C, the collagen fibers are more disorganized and the TEB is rounder in structure (data from Ingman et al 2006). by irradiation before mammary development begins, blocks subsequent mammary development. This developmental block can be overridden by restoration of the bone marrow by transplantation of the irradiated mice, a treatment that results in a complete rescue of the mammary tree.…”

Section: Pubertal Mammary Developmentmentioning

confidence: 99%

“…TEBs are surrounded by a collagenous matrix (Hinck and Silberstein 2005;Schwertfeger et al 2006b) and these structures grow out through a funnel of organized fibers that are composed primarily of fibrillar collagen type 1 (Ingman et al 2006). Intravital imaging of TEBs using multiphoton microscopy of mice expressing green fluorescent protein (GFP) regulated by a Csf1r-promoter (Sasmono et al 2003) show that macrophages travel up and down these fibers at a fast rate and also "jump" between them (Ingman et al 2006).…”

Section: Leukocytes In Mammary Development and Cancermentioning

confidence: 99%