Macrophage Diversity Enhances Tumor Progression and Metastasis

There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression. During tumor initiation, they create an inflammatory environment that is mutagenic and promotes growth. As tumors progress to malignancy, macrophages stimulate angiogenesis, enhance tumor cell migration and invasion, and suppress antitumor immunity. At metastatic sites, macrophages prepare the target tissue for arrival of tumor cells, and then a different subpopulation of macrophages promotes tumor cell extravasation, survival, and subsequent growth. Specialized subpopulations of macrophages may represent important new therapeutic targets.

[1]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[2]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[3]  Jeffrey W Pollard,et al.  Gene Expression Analysis of Macrophages That Facilitate Tumor Invasion Supports a Role for Wnt-Signaling in Mediating Their Activity in Primary Mammary Tumors , 2009, The Journal of Immunology.

[4]  F. Beuvon,et al.  Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. , 1994, Journal of the National Cancer Institute.

[5]  Martin S. Taylor,et al.  The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line , 2009, Nature Genetics.

[6]  Andrew V. Nguyen,et al.  The Macrophage Growth Factor CSF-1 in Mammary Gland Development and Tumor Progression , 2002, Journal of Mammary Gland Biology and Neoplasia.

[7]  Andrew V. Nguyen,et al.  A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis. , 2010, The American journal of pathology.

[8]  A. Sica,et al.  A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood "resident" monocytes, and embryonic macrophages suggests common functions and developmental relationships. , 2009, Blood.

[9]  F. Balkwill Tumour necrosis factor and cancer , 2009, Nature Reviews Cancer.

[10]  J. Hamilton Colony-stimulating factors in inflammation and autoimmunity , 2008, Nature Reviews Immunology.

[11]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[12]  R. Schwendener,et al.  Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach , 2006, British Journal of Cancer.

[13]  D. Hanahan,et al.  Transgenic mouse models of tumour angiogenesis: the angiogenic switch, its molecular controls, and prospects for preclinical therapeutic models. , 1996, European journal of cancer.

[14]  M. Karin,et al.  IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. , 2009, Cancer cell.

[15]  T. Lucas,et al.  Stromal cell‐derived CSF‐1 blockade prolongs xenograft survival of CSF‐1‐negative neuroblastoma , 2009, International journal of cancer.

[16]  Masahiro Inoue,et al.  An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. , 2004, The Journal of clinical investigation.

[17]  B. Kacinski,et al.  The Role of CSF-1 in Normal and Neoplastic Breast Physiology , 1999 .

[18]  J. Pollard Tumour-educated macrophages promote tumour progression and metastasis , 2004, Nature Reviews Cancer.

[19]  J. Pollard,et al.  A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors , 2004, Cancer Research.

[20]  Bojana Gligorijevic,et al.  Dendra2 Photoswitching through the Mammary Imaging Window , 2009, Journal of visualized experiments : JoVE.

[21]  Z. Werb,et al.  New functions for the matrix metalloproteinases in cancer progression , 2002, Nature Reviews Cancer.

[22]  Bethan Psaila,et al.  The metastatic niche: adapting the foreign soil , 2009, Nature Reviews Cancer.

[23]  G. Christofori,et al.  Corrupt policemen: inflammatory cells promote tumor angiogenesis , 2009, Current opinion in oncology.

[24]  J. Pollard Trophic macrophages in development and disease , 2009, Nature Reviews Immunology.

[25]  R. Schwendener,et al.  Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. , 2009, Cancer research.

[26]  Jeffrey W Pollard,et al.  Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. , 2003, The American journal of pathology.

[27]  J. Pollard,et al.  The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin beta1 and CXCL12. , 2009, Cancer research.

[28]  Michael Karin,et al.  References and Notes Supporting Online Material Materials and Methods Som Text Figs. S1 to S6 Tables S1 to S4 Gender Disparity in Liver Cancer Due to Sex Differences in Myd88-dependent Il-6 Production , 2022 .

[29]  A. Mantovani,et al.  Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. , 2007, The Journal of investigative dermatology.

[30]  Hua Yu,et al.  Tumour immunology: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment , 2007, Nature Reviews Immunology.

[31]  M. Miyazaki,et al.  Significance of monocyte chemoattractant protein-1 in angiogenesis and survival in colorectal liver metastases. , 2009, International journal of oncology.

[32]  R. Weinberg,et al.  Systemic Endocrine Instigation of Indolent Tumor Growth Requires Osteopontin , 2008, Cell.

[33]  L. Samson,et al.  DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. , 2008, The Journal of clinical investigation.

[34]  Na Zhang,et al.  Deletion of Vascular Endothelial Growth Factor in myeloid cells accelerates tumorigenesis , 2008, Nature.

[35]  Andrew P. McMahon,et al.  WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature , 2005, Nature.

[36]  J. Roes,et al.  Ulcerative colitis and autoimmunity induced by loss of myeloid alphav integrins. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Segall,et al.  Intravital imaging of cell movement in tumours , 2003, Nature Reviews Cancer.

[38]  B. Mroczko,et al.  Serum levels of granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) in pancreatic cancer patients , 2007, Clinical chemistry and laboratory medicine.

[39]  M. Leach,et al.  Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. , 1996, The Journal of clinical investigation.

[40]  I. Wistuba,et al.  Promotion of lung carcinogenesis by chronic obstructive pulmonary disease-like airway inflammation in a K-ras-induced mouse model. , 2009, American journal of respiratory cell and molecular biology.

[41]  A. Harris,et al.  Tumor-Associated Macrophages in Breast Cancer , 2002, Journal of Mammary Gland Biology and Neoplasia.

[42]  H. Saya,et al.  Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells , 2008, The EMBO journal.

[43]  B. Nielsen,et al.  Reduced metastasis of transgenic mammary cancer in urokinase‐deficient mice , 2005, International journal of cancer.

[44]  I. Fidler,et al.  Recognition and destruction of neoplastic cells by activated macrophages: discrimination of altered self. , 1988, Biochimica et biophysica acta.

[45]  S. Johansson,et al.  Tumour-associated macrophage infiltration, neovascularization and aggressiveness in malignant melanoma: role of monocyte chemotactic protein-1 and vascular endothelial growth factor-A , 2005, Melanoma research.

[46]  J. Pollard,et al.  Tumor-associated macrophages press the angiogenic switch in breast cancer. , 2007, Cancer research.

[47]  Andrew H. Beck,et al.  Tumorigenesis and Neoplastic Progression Coordinate Expression of Colony-Stimulating Factor-1 and Colony-Stimulating Factor-1-Related Proteins Is Associated with Poor Prognosis in Gynecological and Nongynecological Leiomyosarcoma , 2009 .

[48]  A. Harris,et al.  Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer , 2000, The Journal of pathology.

[49]  S. Akira,et al.  Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis , 2008, Proceedings of the National Academy of Sciences.

[50]  J. Pollard,et al.  Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages , 2007, Molecular oncology.

[51]  D. Hanahan,et al.  Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. , 2006, Genes & development.

[52]  John Condeelis,et al.  Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis , 2006, Cell.

[53]  Zhao-You Tang,et al.  High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  Noam Brown,et al.  The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies , 2002, The Journal of pathology.

[55]  L. Coussens,et al.  CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. , 2009, Cancer cell.

[56]  Karey Shumansky,et al.  Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). , 2005, Blood.

[57]  Jae Hyun Kim,et al.  High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer , 2008, British Journal of Cancer.

[58]  R. Jain,et al.  VEGFR1 Activity Modulates Myeloid Cell Infiltration in Growing Lung Metastases but Is Not Required for Spontaneous Metastasis Formation , 2009, PloS one.

[59]  A. Dabrowski,et al.  Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[60]  N. Van Rooijen,et al.  Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model. , 2009, Neoplasia.

[61]  J. Roes,et al.  Ulcerative colitis and autoimmunity induced by loss of myeloid αv integrins , 2007, Proceedings of the National Academy of Sciences.

[62]  G. Natoli,et al.  Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB , 2009, Proceedings of the National Academy of Sciences of the United States of America.

[63]  Yi-Chen Lin,et al.  Tumor-associated macrophages: the double-edged sword in cancer progression. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  Craig Murdoch,et al.  Plasticity in tumor-promoting inflammation: impairment of macrophage recruitment evokes a compensatory neutrophil response. , 2008, Neoplasia.

[65]  J. Joyce,et al.  IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. , 2010, Genes & development.

[66]  Luigi Naldini,et al.  Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. , 2005, Cancer cell.

[67]  A. Sica,et al.  A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). , 2006, Blood.

[68]  Jing Xu,et al.  Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1 , 2009, The Journal of experimental medicine.

[69]  Craig Murdoch,et al.  The role of myeloid cells in the promotion of tumour angiogenesis , 2008, Nature Reviews Cancer.

[70]  M. Karin,et al.  Inhibition of NF-κB in cancer cells converts inflammation- induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression , 2004 .

[71]  A. Mantovani,et al.  Smoldering and polarized inflammation in the initiation and promotion of malignant disease. , 2005, Cancer cell.

[72]  J. Ricarte-Filho,et al.  Increased density of tumor-associated macrophages is associated with decreased survival in advanced thyroid cancer. , 2008, Endocrine-related cancer.

[73]  J. Pollard,et al.  The role of colony-stimulating factor 1 and its receptor in the etiopathogenesis of endometrial adenocarcinoma. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[74]  Andrew H. Beck,et al.  Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ , 2010, Breast Cancer Research and Treatment.

[75]  Michael Karin,et al.  IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer , 2004, Cell.

[76]  G. Trinchieri,et al.  Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. , 2005, Cancer research.

[77]  I. Weissman,et al.  CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis , 2009, Cell.

[78]  Andrew H. Beck,et al.  The Macrophage Colony-Stimulating Factor 1 Response Signature in Breast Carcinoma , 2009, Clinical Cancer Research.

[79]  Michael C. Ostrowski,et al.  An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. , 2010, Cancer research.

[80]  B. O’Malley,et al.  Disruption of the SRC-1 gene in mice suppresses breast cancer metastasis without affecting primary tumor formation , 2009, Proceedings of the National Academy of Sciences.

[81]  N. Van Rooijen,et al.  Macrophages mediate inflammation-enhanced metastasis of ovarian tumors in mice. , 2007, Cancer research.

[82]  G. Nuovo,et al.  Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. , 2009, Cancer research.

[83]  A. Darzi,et al.  Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer , 2007, Clinical & Experimental Metastasis.

[84]  C. Lewis,et al.  Inflammation and breast cancer. Microenvironmental factors regulating macrophage function in breast tumours: hypoxia and angiopoietin-2 , 2007, Breast Cancer Research.

[85]  Jiasen Cheng,et al.  Human macrophages promote the motility and invasiveness of osteopontin-knockdown tumor cells. , 2007, Cancer research.

[86]  N. Minato,et al.  SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion , 2007, Nature Genetics.

[87]  Andrew V. Nguyen,et al.  Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy , 2001, The Journal of experimental medicine.

[88]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[89]  H. Saji,et al.  Significant correlation of monocyte chemoattractant protein‐1 expression with neovascularization and progression of breast carcinoma , 2001, Cancer.

[90]  J. Kurebayashi,et al.  The expression of monocyte chemotactic protein-1 in papillary thyroid carcinoma is correlated with lymph node metastasis and tumor recurrence. , 2009, Thyroid : official journal of the American Thyroid Association.

[91]  J. Pollard,et al.  Macrophages regulate the angiogenic switch in a mouse model of breast cancer. , 2006, Cancer research.

[92]  L. Trümper,et al.  Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[93]  S. Subramaniam,et al.  Chemoattractant Signaling between Tumor Cells and Macrophages Regulates Cancer Cell Migration, Metastasis and Neovascularization , 2009, PloS one.

[94]  M. Shibuya,et al.  MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. , 2002, Cancer cell.

[95]  M. Colombo,et al.  Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. , 2008, Cancer research.

[96]  John S. Condeelis,et al.  Tumor Microenvironment of Metastasis in Human Breast Carcinoma: A Potential Prognostic Marker Linked to Hematogenous Dissemination , 2009, Clinical Cancer Research.

[97]  Wan-Wan Lin,et al.  Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis , 2009, Nature.

[98]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[99]  F. Alt,et al.  Deficiencies of GM-CSF and Interferon γ Link Inflammation and Cancer , 2003, The Journal of experimental medicine.

[100]  G. Meijer,et al.  Macrophages direct tumour histology and clinical outcome in a colon cancer model , 2005, The Journal of pathology.

[101]  Mouldy Sioud,et al.  Targeting stromal-cancer cell interactions with siRNAs. , 2009, Methods in molecular biology.

[102]  William King,et al.  High-density gene expression analysis of tumor-associated macrophages from mouse mammary tumors. , 2009, The American journal of pathology.

[103]  S. Tannenbaum,et al.  Lipid peroxidation dominates the chemistry of DNA adduct formation in a mouse model of inflammation. , 2007, Carcinogenesis.

[104]  J. Pollard,et al.  Microenvironmental regulation of metastasis , 2009, Nature Reviews Cancer.

[105]  S. Gordon Alternative activation of macrophages , 2003, Nature Reviews Immunology.

[106]  Michael Karin,et al.  NF-kappaB: linking inflammation and immunity to cancer development and progression. , 2005, Nature reviews. Immunology.

[107]  G. Fleuren,et al.  The absence of CCL2 expression in cervical carcinoma is associated with increased survival and loss of heterozygosity at 17q11.2 , 2006, The Journal of pathology.

[108]  J. Erler,et al.  Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. , 2009, Cancer cell.

[109]  S. Vandenberg,et al.  HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. , 2008, Cancer cell.

[110]  Wan-Wan Lin,et al.  A cytokine-mediated link between innate immunity, inflammation, and cancer. , 2007, The Journal of clinical investigation.

[111]  Ruth J. Muschel,et al.  A Distinct Macrophage Population Mediates Metastatic Breast Cancer Cell Extravasation, Establishment and Growth , 2009, PloS one.

[112]  T. Hagemann,et al.  Macrophages Induce Invasiveness of Epithelial Cancer Cells Via NF-κB and JNK1 , 2005, The Journal of Immunology.

[113]  J. J. Visser,et al.  Enhanced tumour growth in the rat liver after selective elimination of Kupffer cells , 1993, Cancer Immunology, Immunotherapy.

[114]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[115]  V. Nizet,et al.  Innate Immunity Gone Awry: Linking Microbial Infections to Chronic Inflammation and Cancer , 2006, Cell.

[116]  Alberto Mantovani,et al.  Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. , 2009, Carcinogenesis.

[117]  F. Balkwill,et al.  Endothelin‐2 is a macrophage chemoattractant: implications for macrophage distribution in tumors , 2002, European journal of immunology.

[118]  Hiroyuki Aburatani,et al.  The S100A8–serum amyloid A3–TLR4 paracrine cascade establishes a pre-metastatic phase , 2008, Nature Cell Biology.

[119]  Hiroyuki Aburatani,et al.  Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis , 2006, Nature Cell Biology.

[120]  M. Miyazaki,et al.  Stromal MCP‐1 in mammary tumors induces tumor‐associated macrophage infiltration and contributes to tumor progression , 2009, International journal of cancer.

[121]  J. Pollard,et al.  Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[122]  Alberto Mantovani,et al.  Macrophages, innate immunity and cancer: balance, tolerance, and diversity. , 2010, Current opinion in immunology.

[123]  S. Akira,et al.  Macrophage/Cancer Cell Interactions Mediate Hormone Resistance by a Nuclear Receptor Derepression Pathway , 2006, Cell.

[124]  Yarong Wang,et al.  Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. , 2007, Cancer research.

[125]  O. Vasiljeva,et al.  Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. , 2006, Cancer research.

[126]  Jeffrey Wyckoff,et al.  Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. , 2009, Cancer research.