Myeloid cells in tumor inflammation
© Schmid and Varner; licensee BioMed Central Ltd. 2012
Received: 21 June 2012
Accepted: 25 June 2012
Published: 3 September 2012
Bone marrow derived myeloid cells progressively accumulate in tumors, where they establish an inflammatory microenvironment that is favorable for tumor growth and spread. These cells are comprised primarily of monocytic and granulocytic myeloid derived suppressor cells (MDSCs) or tumor-associated macrophages (TAMs), which are generally associated with a poor clinical outcome. MDSCs and TAMs promote tumor progression by stimulating immunosuppression, neovascularization, metastasis and resistance to anti-cancer therapy. Strategies to target the tumor-promoting functions of myeloid cells could provide substantial therapeutic benefit to cancer patients.
KeywordsMacrophage Myeloid derived suppressor cells Tumor angiogenesis Tumor microenvironment Tumor inflammation Cancer
Inflammation and cancer
Chronic inflammation is a causative or exacerbating factor in a host of complex human diseases, including solid tumors and leukemias/lymphomas, chronic bacterial and parasitic infections, rheumatoid arthritis, Crohn’s disease, asthma and central nervous system (CNS) disorders such as Alzheimers’ disease, Parkinson’s disease and multiple sclerosis. In each of these diseases, affected tissues are heavily invested with inflammatory myeloid cells, which include resident or bone marrow derived macrophages [1–4]. In addition, all tumors are heavily invested with myeloid cells, including tumor-associated macrophages (TAMs) [5, 6]. Myeloid cells stimulate cancer initiation, malignant progression, metastasis and resistance to therapy . Thus, targeting molecular pathways regulating the tumor promoting functions of myeloid cells holds promise for solid tumor therapy.
Macrophages in normal and tumor biology
Macrophages are myeloid lineage cells that arise from bone marrow derived monocytic progenitor cells that differentiate into tissue macrophages, antigen-presenting dendritic cells and bone resorbing osteoclasts [8, 9]. Macrophages can be activated in response to environmental signals, including microbial products and cytokines. Activated macrophages can be loosely divided into M1 (classically activated) and M2 (alternatively activated) phenotype . Classical activation occurs in response to bacterial moieties such as lipopolysacharide (LPS) and immune stimuli such as interferon γ (IFNγ). M1 macrophages mediate resistance against intracellular parasites and tumors and elicit tissue disruptive reactions by secreting tumoricidal agents such as tumor necrosis factor α (TNF-α), interleukin-12 (IL-12), and reactive nitrogen and oxygen intermediates (RNI, ROI). In addition, M1 macrophages promote T-helper-l (Thl) responses. In general, M2 macrophages exhibit an immunosuppressive phenotype and release factors that include IL-l0 and Arginase-1 [10, 11].
M2 macrophages are the predominant type of macrophage found in tumors . M1 macrophages are abundant at sites of chronic inflammation and in early tumors [12, 13], but then switch to an M2-like phenotype during tumor progression [14–16]. Although IL-4, IFNγ, and several other tumor-derived cytokines and growth factors modulate macrophage phenotypes in vitro and in vivo[1, 17], the molecular mechanisms that promote M1 or M2 TAM subsets within the tumor microenvironment are incompletely understood.
Although TAMs can convert into M1 or M2 phenotypes, and thereby execute almost diametrically opposed biological functions, unique cell surface markers that distinguish the two TAM phenotypes remain elusive. Flow cytometric analysis does indicate that M1-like TAMs express an F4/80 + CD11c+MRClow phenotype, while M2-like TAMs express an F4/80 + CD11cnegMRChigh phenotype .
Myeloid derived suppressor cells
Myeloid derived suppressor cells (MDSC) are CD11b+Gr1+ immunosuppressive, incompletely differentiated myeloid progenitor cells originally identified in tumor bearing mice . MDSC accumulate in the blood, spleen, lymph nodes, bone marrow and tumors of tumor-bearing animals and patients [20–24]. MDSCs inhibit innate and adaptive immunity, promoting tumor immune escape. MDSC are a heterogeneous population of cells that lack the expression of cell surface markers that are specifically expressed on macrophages or DC . In mice, MDSC are uniformly characterized by the expression of Gr1 and CD11b. Gr1 includes the macrophage and neutrophil markers Ly6C and Ly6G, respectively, whereas CD11b (also known as integrin αM) is characteristic for the myeloid- cell linage. In recent years, several other surface molecules have been used to identify additional subset of immunosuppressive MDSC, including CD80 , CD115 (also known as macrophage colony stimulating factor (M-CSF) receptor) and CD124 (IL-4 receptor alpha chain, IL-4Rα) . In addition, nuclear morphology has also been used to characterize mouse MDSC. Mononuclear CDllb+Gr1midLy6G+/−Ly6ChighCD49d+ cells are considered “monocytic” whereas polymorphonuclear CDllb+Gr1highLy6G+Ly6CnegCD49dneg MDSC are considered granulocytic [28–30]. Subpopulations of MDSC can give rise to CD11b+Gr1lowF4/80+MHCII+ macrophages with potent immunosuppressive properties, underscoring the potential biological continuum of immature myeloid cells, monocytes, and macrophages [20, 25, 31].
In patients with glioblastoma, breast cancer, colon cancer, lung cancer or kidney cancer, MDSC have been defined as LinnegCDllb+HLA-DRnegCD33+ cells that express the common myeloid marker CD33 but lack mature monocyte and lymphoid cell linage markers (Linneg = CD14neg, CD3neg, CD19neg) and lack the MHC class II molecule HLA-DR . In patients with renal cancer, polymorphonuelcar MDSC have been shown to express CD11b+ CD14negCD15+CD66b+ VEGFR1+ whereas in patients with melanoma, prostate cancer, hepatocellular carcinoma or head and neck cancer, immunosuppressive monocytic CD11b+ CD14+ HLA-DRlow/neg MDSC were found [21, 34–36]. These cells are associated with increased tumor burden and poor prognosis in patients with breast and colorectal cancer [24, 37].
Mechanisms of myeloid cell recruitment
Immune cell trafficking in vivo is regulated by chemokines and cytokines, and by members of the integrin, immunoglobulin and selectin adhesion molecule families [38, 39]. A diverse array of chemotactic factors that are expressed either by tumor cells or tumor infiltrating immune cells stimulate myeloid cell recruitment into tumors. These factors include CCL2 (MIP-1), CCL5 (RANTES), CCL12, IL-8, IL-lβ, CXCL12 (SDF-1α), and CXCL5 (ENA-78) [40–44].
While malignant tumor cells express myeloid cell chemoattractants, tumor infiltrating immune cells also express a variety of chemotactic factors, which can further foster myeloid cell recruitment and accumulation in the tumor microenvironment. For example, myeloid cell derived IL-1β stimulates myeloid cell recruitment in vivo and pharmacological inhibition of IL-1β reduced the infiltration of myeloid cells into the tumor microenvironment and inhibited tumor progression in a lung cancer tumor model . Tumor derived factors, such as G-CSF, can also stimulate long-range effects in the bone marrow, leading to myeloid cell expression of Bv8, a factor that stimulates myelopoiesis and mobilization [45, 46].
Recent efforts have also been made to identify tumor-derived factors that specifically recruit myeloid cells in response to chemotherapeutic treatments. CCL2 and CCL12 were highly upregulated in doxorubicin treated MMTV-PyMT animals; genetic depletion of CCR2 or pharmacological blockade of GPCR-mediated signaling with pertussis toxin, reduced myeloid cell recruitment in response to chemotherapy and increased the sensitivity of tumors . Paclitaxel treatment of MMTV-PyMT animals induced colony stimulating factor 1 (CSF-l) and IL-34 expression, which together stimulated CSF1 receptor (CSF1R)-dependent macrophage infiltration . Blockade of CSF1R signaling in combination with paclitaxel improved survival of mammary tumor-bearing mice. Myeloid cells thus play a central role in resistance to chemotherapy.
Roles of integrins in myeloid cell recruitment
The integrin adhesion molecule family is an extensive group of structurally related receptors for extracellular matrix (ECM) proteins and immunoglobulin superfamily molecules. Integrins are divalent cation-dependent heterodimeric membrane glycoproteins comprised of non-covalently associated α and β subunits that promote cell attachment and migration on the surrounding extracellular matrix. Eighteen α and eight β subunits can associate to form twenty-four unique integrin heterodimers [48, 49]. Integrins on bone marrow-derived immune cells promote tumor inflammation by facilitating myeloid cell trafficking to the tumor microenvironment [42, 50, 51]. Myeloid cells express a number of functional integrins, including α2β1, α4β1, α5β1, αvβ3, αvβ5, αMβ2 (CD11b) and αXβ2 (CD11c) [52–54]. Recent studies from our laboratory indicate that integrin α4β1, a receptor for vascular cell adhesion molecule 1 (VCAM-1) and CS-l fibronectin, selectively promotes the homing of myeloid cells to the tumor microenvironment [42, 55]. Human and murine myeloid cells adhered to endothelial cells in vitro and to tumor endothelium in vivo via integrin α4β1. Genetic and pharmacological blockade of integrin α4βl significantly suppressed tumor inflammation, growth and metastasis. In addition, combination of anti-integrin α4 antibody and chemotherapeutic agents markedly reduced tumor burden compared to chemotherapeutic treatment alone . Thus, these studies indicate that suppression of myeloid cell trafficking to the tumor microenvironment with integrin α4βl antagonists could be a useful adjuvant approach in cancer therapy.
Signaling molecules in myeloid cell recruitment
Roles of myeloid cells in tumor progression
MDSC and TAMs are both major regulators of the immune response .
MDSC suppress T cell proliferation in part by expression of Arginase-1 . L-arginine plays a critical role in the inhibition of cytotoxic T cells by MDSC. Arginase converts L-arginine into L-ornithine and urea, thereby depleting L-arginine from the microenvironment and preventing iNOS from converting L-arginine to NO, an immunostimulant . Depletion of arginine by Arginase I inhibits expression of the T-Cell Receptor (TCR) CD3zeta chain and T cell proliferation . MDSC produced ROS also inhibits CD8+ T cell function by catalyzing the nitration of the TCR and thereby preventing T cell peptide-MHC interactions . Moreover, several known tumor-derived factors, such as TGF-β, IL-3, IL-6, IL-l0, Platelet derived growth factor β, and granulocyte macrophage colony stimulating factor (GM-CSF) can induce the production of ROS by MDSC [8, 72].
Beside inhibition of T cell activation, MDSC secrete immune suppressive cytokine with can inhibit immune surveillance. Secretion of the type 2 cytokine IL-l0 down-regulates the production of the type 1 cytokine IL-12 in macrophages. In addition, IL-l0 and VEGF-A inhibit the maturation of DC . TGF-β has also been associated with MDSC immune suppressive functions. In fibrosarcoma and colon carcinoma tumor models, MDSC produced TGF-β in response to IL-13 stimulation, which resulted in decreased tumor immunosurveillance of cytotoxic T –cells [73, 74].
Myeloid cells in relapse or resistance to therapy
CD11b+Grl+ myeloid cells and TAMs play key roles in regulating the response of tumors to therapy, including anti-angiogenic and chemotherapeutic treatments. Accumulation of CD11b+Grl+ cells in tumors inhibits responsiveness to anti-angiogenic blockade by anti-VEGF-A antibodies . Bv8, a protein expressed by myeloid cells in the bone marrow, stimulated the expansion and mobilization of CD11b+Grl+ cells in the bone marrow and mediated resistance to anti-VEGFA therapy [76, 77].
Macrophages and anti-cancer therapy
The significance of the vascular remodeling functions of TAMs in cancer therapy has recently emphasized by several studies. Tumor blood vessels are mostly disorganized and immature compared to non-pathological angiogenesis. Blood vessels are more torturous, with reduced pericyte coverage, and reduced erratic blood flow . A recent studied showed that blood vessel normalization can be modulated by targeting the angiopoietin/Tie2 pathway. Interestingly, the angiopoietin receptor Tie2 is not only expressed on endothelial cells, but also a subpopulation of tumor infiltrating macrophages with vascular remodeling function. Targeting the Angiopoietin/Tie2 pathway by a fully humanized anti-ANG2 monoclonal antibody inhibited tumor angiongenesis, growth, and metastasis, and disabled the pro-angiogenic functions of tumor infiltrating macrophages, thus impeding the emergence of evasive resistance to anti-angiogenic therapy . Genetic depletion of VEGF-A gene under the macrophage specific promoter LysM-Cre attenuates tumor angiogenesis and results in a morphologically more normal vasculature___. Tumors with normalized blood vessels showed increased sensitivity to chemotherapeutic treatment . Similarly, histidine-rich glycoprotein HRG, a host-produced protein deposited in tumor stroma, can induce a reprogramming of the vascular remodeling functions of TAMs, resulting in vascular normalization and improved responses to chemotherapy . In another report, blockade of CSF-1 signaling in a breast cancer tumor model, resulted in reduced numbers of intra-tumoral macrophage, normalized tumor vasculature, and increased responses to chemotherapy . Notably, beside vascular normalization, both studies also showed enhanced anti-tumor immune responses, thus indicating the complexity of crosstalk’s by diverse cell types within the tumor microenvironment, and the power of targeting one subtype to thereby subvert biological functions of other stromal cells.
A mechanism independent of vascular normalization was proposed by Johanna Joyce and colleagues. The authors identified that TAMs secreted factors that protect tumors from chemotherapy. In the PyMT breast cancer models, tumors treated with the chemotoxic agent paclitaxel had more TAMs than control tumors. These TAMs expressed increased levels of proteases, specifically cysteine cathepsin B. Expression of cathepsin B was suggested to be necessary to protect cancer cells in vitro and in vivo from several chemotoxic agents, including paclitaxel, etoposide, and doxorubicin .
Myeloid cells promote tumor progression and alter the response of tumors to anti-cancer therapies. Identification and targeting of myeloid cells represents an emerging and attractive therapeutic approach to fight cancer. Therapeutic strategies targeting TAMs include inhibition of their recruitment to the tumor microenvironment, blockade of their pro-tumoral effector functions, and reprogramming of macrophage/MDSC polarization and thus restoring their anti-tumorigenic functions. Targeting myeloid cell recruitment can reduce tumor progression and improve the efficacy of chemotherapeutic treatments [41, 51]. Similarly, partial reprogramming of macrophage polarization towards an M1-like phenotype enhances chemotherapy and reduces tumor growth [18, 82]. Importantly, some of the anti-tumorigenic functions of macrophages critically depend on the presence of cytotoxic CD8+ T-cells, which are part of the adaptive immune system [47, 83].
- Biswas SK, Mantovani A: Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010,11(10):889–896.PubMedView Article
- Grivennikov SI, Greten FR, Karin M: Immunity, inflammation, and cancer. Cell 2010,140(6):883–899.PubMedView Article
- Murray PJ, Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011,11(11):723–737.PubMedView Article
- Wynn TA, Barron L: Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 2010,30(3):245–257.PubMedView Article
- Mantovani A, et al.: Cancer-related inflammation. Nature 2008,454(7203):436–444.PubMedView Article
- Mantovani A, Sica A: Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010,22(2):231–237.PubMedView Article
- Hanahan D, Coussens LM: Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012,21(3):309–322.PubMedView Article
- Gabrilovich DI, Ostrand-Rosenberg S, Bronte V: Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012,12(4):253–268.PubMedView Article
- Geissmann F, et al.: Development of monocytes, macrophages, and dendritic cells. Science 2010,327(5966):656–661.PubMedView Article
- Karp CL, Murray PJ: Non-canonical alternatives: what a macrophage is 4. J Exp Med 2012,209(3):427–431.PubMedView Article
- Gordon S, Martinez FO: Alternative activation of macrophages: mechanism and functions. Immunity 2010,32(5):593–604.PubMedView Article
- Greten FR, et al.: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004,118(3):285–296.PubMedView Article
- Karin M, Greten FR: NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005,5(10):749–759.PubMedView Article
- Lin EY, et al.: Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 2006,66(23):11238–11246.PubMedView Article
- Qian B, et al.: A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 2009,4(8):e6562.PubMedView Article
- Ruffell B, Affara NI, Coussens LM: Differential macrophage programming in the tumor microenvironment. Trends Immunol 2012,33(3):119–126.PubMedView Article
- Qian BZ, Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell 2010,141(1):39–51.PubMedView Article
- Rolny C, et al.: HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 2011,19(1):31–44.PubMedView Article
- Peranzoni E, et al.: Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol 2010,22(2):238–244.PubMedView Article
- Bronte V, et al.: Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells. Blood 2000,96(12):3838–3846.PubMed
- Mandruzzato S, et al.: IL4Ralpha + myeloid-derived suppressor cell expansion in cancer patients. J Immunol 2009,182(10):6562–6568.PubMedView Article
- Corzo CA, et al.: HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 2010,207(11):2439–2453.PubMedView Article
- Corzo CA, et al.: Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 2009,182(9):5693–5701.PubMedView Article
- Diaz-Montero CM, et al.: Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 2009,58(1):49–59.PubMedView Article
- Movahedi K, et al.: Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 2008,111(8):4233–4244.PubMedView Article
- Yang R, et al.: CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1 + CD11b + myeloid cells. Cancer Res 2006,66(13):6807–6815.PubMedView Article
- Gallina G, et al.: Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J Clin Invest 2006,116(10):2777–2790.PubMedView Article
- Sawanobori Y, et al.: Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. Blood 2008,111(12):5457–5466.PubMedView Article
- Youn JI, et al.: Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol 2008,181(8):5791–5802.PubMed
- Haile LA, et al.: CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. J Immunol 2010,185(1):203–210.PubMedView Article
- Van Ginderachter JA, et al.: Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands reverse CTL suppression by alternatively activated (M2) macrophages in cancer. Blood 2006,108(2):525–535.PubMedView Article
- Almand B, et al.: Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol 2001,166(1):678–689.PubMed
- Ochoa AC, et al.: Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res 2007,13(2 Pt 2):721s-726s.PubMedView Article
- Filipazzi P, et al.: Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 2007,25(18):2546–2553.PubMedView Article
- Hoechst B, et al.: A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 2008,135(1):234–243.PubMedView Article
- Vuk-Pavlovic S, et al.: Immunosuppressive CD14 + HLA-DRlow/- monocytes in prostate cancer. Prostate 2010,70(4):443–455.PubMed
- Solito S, et al.: A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 2011,118(8):2254–2265.PubMedView Article
- Luster AD, Alon R, von Andrian UH: Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 2005,6(12):1182–1190.PubMedView Article
- Weber C, Koenen RR: Fine-tuning leukocyte responses: towards a chemokine’interactome’. Trends Immunol 2006,27(6):268–273.PubMedView Article
- Du R, et al.: HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008,13(3):206–220.PubMedView Article
- Nakasone ES, et al.: Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 2012,21(4):488–503.PubMedView Article
- Schmid MC, et al.: Combined blockade of integrin-alpha4beta1 plus cytokines SDF-1alpha or IL-1beta potently inhibits tumor inflammation and growth. Cancer Res 2011,71(22):6965–6975.PubMedView Article
- Yang L, et al.: Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1 + CD11b + myeloid cells that promote metastasis. Cancer Cell 2008,13(1):23–35.PubMedView Article
- Wang XQ, et al.: The high level of RANTES in the ectopic milieu recruits macrophages and induces their tolerance in progression of endometriosis. J Mol Endocrinol 2010,45(5):291–299.PubMedView Article
- Shojaei F, et al.: G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci U S A 2009,106(16):6742–6747.PubMedView Article
- Shojaei F, et al.: Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 2007,450(7171):825–831.PubMedView Article
- Denardo DG, et al.: Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy. Cancer Discov 2011, 1:54–67.PubMedView Article
- Shimizu Y, Rose DM, Ginsberg MH: Integrins in the immune system. Adv Immunol 1999, 72:325–380.PubMedView Article
- Shattil SJ, Kim C, Ginsberg MH: The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 2010,11(4):288–300.PubMedView Article
- Ley K, et al.: Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007,7(9):678–689.PubMedView Article
- Schmid MC, et al.: Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 2011,19(6):715–727.PubMedView Article
- Avraamides CJ, Garmy-Susini B, Varner JA: Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 2008,8(8):604–617.PubMedView Article
- Desgrosellier JS, Cheresh DA: Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010,10(1):9–22.PubMedView Article
- Foubert P, Varner JA: Integrins in tumor angiogenesis and lymphangiogenesis. Methods Mol Biol 2012, 757:471–486.PubMedView Article
- Jin H, et al.: Integrin alpha4beta1 promotes monocyte trafficking and angiogenesis in tumors. Cancer Res 2006,66(4):2146–2152.PubMedView Article
- Luque A, et al.: Activated conformations of very late activation integrins detected by a group of antibodies (HUTS) specific for a novel regulatory region (355–425) of the common beta 1 chain. J Biol Chem 1996,271(19):11067–11075.PubMedView Article
- Arnaout MA, Mahalingam B, Xiong JP: Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 2005, 21:381–410.PubMedView Article
- Ye F, et al.: Recreation of the terminal events in physiological integrin activation. J Cell Biol 2010,188(1):157–173.PubMedView Article
- Ye F, Kim C, Ginsberg MH: Reconstruction of integrin activation. Blood 2012,119(1):26–33.PubMedView Article
- Feral CC, et al.: Blocking the alpha 4 integrin-paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site. J Clin Invest 2006,116(3):715–723.PubMedView Article
- Manevich E, et al.: Talin 1 and paxillin facilitate distinct steps in rapid VLA-4-mediated adhesion strengthening to vascular cell adhesion molecule 1. J Biol Chem 2007,282(35):25338–25348.PubMedView Article
- Lewis JS, et al.: Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. J Pathol 2000,192(2):150–158.PubMedView Article
- Sunderkotter C, et al.: Macrophages and angiogenesis. J Leukoc Biol 1994,55(3):410–422.PubMed
- Giraudo E, Inoue M, Hanahan D: An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 2004,114(5):623–633.PubMed
- Hildenbrand R, et al.: Urokinase and macrophages in tumour angiogenesis. Br J Cancer 1995,72(4):818–823.PubMedView Article
- Esposito I, et al.: Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 2004,57(6):630–636.PubMedView Article
- Huang S, et al.: Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J Natl Cancer Inst 2002,94(15):1134–1142.PubMedView Article
- Ostrand-Rosenberg S, Sinha P: Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009,182(8):4499–4506.PubMedView Article
- Munder M: Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol 2009,158(3):638–651.PubMedView Article
- Rodriguez PC, et al.: L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 2003,171(3):1232–1239.PubMed
- Nagaraj S, et al.: Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 2007,13(7):828–835.PubMedView Article
- Sauer H, Wartenberg M, Hescheler J: Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem 2001,11(4):173–186.PubMedView Article
- Fichtner-Feigl S, et al.: Restoration of tumor immunosurveillance via targeting of interleukin-13 receptor-alpha 2. Cancer Res 2008,68(9):3467–3475.PubMedView Article
- Terabe M, et al.: Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 2003,198(11):1741–1752.PubMedView Article
- Shojaei F, et al.: Tumor refractoriness to anti-VEGF treatment is mediated by CD11b + Gr1+ myeloid cells. Nat Biotechnol 2007,25(8):911–920.PubMedView Article
- Qu X, et al.: Induction of Bv8 expression by granulocyte-colony stimulating factor in CD11b + Gr1+ cells: Key role of Stat3 signaling. J Biol Chem 2012,287(23):19574–19584.PubMedView Article
- Shojaei F, et al.: Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci U S A 2008,105(7):2640–2645.PubMedView Article
- Jain RK: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005,307(5706):58–62.PubMedView Article
- Mazzieri R, et al.: Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 2011,19(4):512–526.PubMedView Article
- Stockmann C, et al.: Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature 2008,456(7223):814–818.PubMedView Article
- Shree T, et al.: Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 2011,25(23):2465–2479.PubMedView Article
- Squadrito ML, et al.: miR-511–3p Modulates Gentic Programs of Tumor-Associated Macrophages. Cell Reports 2012, 1:141–154.PubMedView Article
- DeNardo DG, et al.: CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 2009,16(2):91–102.PubMedView Article
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