Studies of postpartum mammary gland involution reveal novel pro-metastatic mechanisms

Abstract

Postpartum involution is the process by which the lactating mammary gland returns to the pre-pregnant state after weaning. Expression of tumor-promotional collagen, upregulation of matrix metalloproteinases, infiltration of M2 macrophages, and remodeling of blood and lymphatic vasculature are all characteristics shared by the involuting mammary gland and breast tumor microenvironment. The tumor promotional nature of the involuting mammary gland is perhaps best evidenced by cases of postpartum breast cancer (PPBC), or those cases diagnosed within 10 years of most recent childbirth. Women with PPBC experience more aggressive disease and higher risk of metastasis than nulliparous patients and those diagnosed outside the postpartum window. Semaphorin 7a (SEMA7A), cyclooxygenase-2 (COX-2), and collagen are all expressed in the involuting mammary gland and, together, predict for decreased metastasis free survival in breast cancer. Studies investigating the role of these proteins in involution have been important for understanding their contributions to PPBC. Postpartum involution thus represents a valuable model for the identification of novel molecular drivers of PPBC and classical cancer hallmarks. In this review, we will highlight the similarities between involution and cancer in the mammary gland, and further define the contribution of SEMA7A/COX-2/collagen interplay to postpartum involution and breast tumor progression and metastasis.

Keywords

Postpartum involution / postpartum breast cancer / Semaphorin 7a / cyclooxygenase-2 / collagen / metastasis

References

[1] Perou CM,Eisen MB,Jeffrey SS.Molecular portraits of human breast tumours..Nature2000;406:747-52

[2] Masoud V.Targeted therapies in breast cancer: new challenges to fight against resistance..World J Clin Oncol2017;8:120-34 PMCID:PMC5385433

[3] Liedtke C,Hess KR,Tordai A.Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer..J Clin Oncol2008;26:1275-81

[4] Bauer KR,Cress RD,Caggiano V.Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry..Cancer2007;109:1721-8

[5] Albrektsen G,Kvale G.The short-term and long-term effect of a pregnancy on breast cancer risk: a prospective study of 802,457 parous Norwegian women..Br J Cancer1995;72:480-4 PMCID:PMC2033982

[6] Lambe M,Trichopoulos D,Pavia M.Transient increase in the risk of breast cancer after giving birth..N Engl J Med1994;331:5-9

[7] Lyons TR,Borges VF.Pregnancy and breast cancer: when they collide..J Mammary Gland Biol Neoplasia2009;14:87-98 PMCID:PMC2693784

[8] Nichols HB,Cai J,Wright LB.Breast cancer risk after recent childbirth: a pooled analysis of 15 prospective studies..Ann Intern Med2018;

[9] Schedin P.Pregnancy-associated breast cancer and metastasis..Nat Rev Cancer2006;6:281-91

[10] Callihan EB,Jindal S,Manthey E.Postpartum diagnosis demonstrates a high risk for metastasis and merits an expanded definition of pregnancy-associated breast cancer..Breast Cancer Res Treat2013;138:549-59 PMCID:PMC3608871

[11] Leon DA,Broeders MJ,Murphy MF.Breast cancer in Swedish women before age 50: evidence of a dual effect of completed pregnancy..Cancer Causes Control1995;6:283-91

[12] Janerich DT.Evidence for a crossover in breast cancer risk factors..Am J Epidemiol1982;116:737-42

[13] Goddard ET,Schedin T,Johnston J.Association between postpartum breast cancer diagnosis and metastasis and the clinical features underlying risk..JAMA Netw Open2019;2:e186997

[14] Asztalos S,Hayes MK,Beam CA.Gene expression patterns in the human breast after pregnancy..Cancer Prev Res (Phila)2010;3:301-11

[15] Guo Q,Burchard J,Spellman P.Physiologically activated mammary fibroblasts promote postpartum mammary cancer..JCI Insight2017;2:e89206 PMCID:PMC5358521

[16] Lyons TR,Betts CB,Kapoor P.Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer..J Clin Invest2014;124:3901-12 PMCID:PMC4153700

[17] McCready J,Rudnick JA.The contribution of dynamic stromal remodeling during mammary development to breast carcinogenesis..Breast Cancer Res2010;12:205 PMCID:PMC2917019

[18] Lyons TR,Borges VF,Keely PJ.Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2..Nat Med2011;17:1109-15 PMCID:PMC3888478

[19] Martinson HA,Durand-Rougely C,Schedin P.Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression..Int J Cancer2015;136:1803-13 PMCID:PMC4324053

[20] O’Brien J,Monks J,Wilson RS.Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species..Am J Pathol2010;176:1241-55 PMCID:PMC2832146

[21] O’Brien J.Macrophages in breast cancer: do involution macrophages account for the poor prognosis of pregnancy-associated breast cancer?.J Mammary Gland Biol Neoplasia2009;14:145-57 PMCID:PMC2693782

[22] Gupta PB,Cingoz O,Naber SP.Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers..Cancer Res2007;67:2062-71

[23] Macias H.Mammary gland development..Wiley Interdiscip Rev Dev Biol2012;1:533-57 PMCID:PMC3404495

[24] Balinsky BI.On the prenatal growth of the mammary gland rudiment in the mouse..J Anat1950;84:227-35 PMCID:PMC1273299

[25] Monaghan P,Cowen P.Peripubertal human breast development..Anat Rec1990;226:501-8

[26] Oakes SR,Ormandy CJ.The alveolar switch: coordinating the proliferative cues and cell fate decisions that drive the formation of lobuloalveoli from ductal epithelium..Breast Cancer Res2006;8:207 PMCID:PMC1557712

[27] Haaksma CJ,Tomasek JJ.Myoepithelial cell contraction and milk ejection are impaired in mammary glands of mice lacking smooth muscle alpha-actin..Biol Reprod2011;85:13-21 PMCID:PMC3123380

[28] Lu P,Werb Z.The extracellular matrix: a dynamic niche in cancer progression..J Cell Biol2012;196:395-406 PMCID:PMC3283993

[29] Pickup MW,Weaver VM.The extracellular matrix modulates the hallmarks of cancer..EMBO Rep2014;15:1243-53 PMCID:PMC4264927

[30] Mouw JK,Weaver VM.Extracellular matrix assembly: a multiscale deconstruction..Nat Rev Mol Cell Biol2014;15:771-85 PMCID:PMC4682873

[31] Schedin P.Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression..Cold Spring Harb Perspect Biol2011;3:a003228 PMCID:PMC3003460

[32] Keely PJ,Zutter MM.Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense alpha 2 integrin mRNA in mammary cells..J Cell Sci1995;108:595-607

[33] Chen J,Grenache DG,Zutter MM.The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis..Am J Pathol2002;161:337-44 PMCID:PMC1850700

[34] van ‘t Veer LJ,van de Vijver MJ,Hart AA.Gene expression profiling predicts clinical outcome of breast cancer..Nature2002;415:530-6

[35] Provenzano PP,Eliceiri KW,Yan L.Collagen density promotes mammary tumor initiation and progression..BMC medicine2008;6:11 PMCID:PMC2386807

[36] Vane JR.Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs..Nat New Biol1971;231:232-5

[37] Funk CD.Prostaglandins and leukotrienes: advances in eicosanoid biology..Science2001;294:1871-5

[38] Smith WL,Garavito RM.Cyclooxygenases: structural, cellular, and molecular biology..Annu Rev Biochem2000;69:145-82

[39] Cha YI,DuBois RN.Fishing for prostanoids: deciphering the developmental functions of cyclooxygenase-derived prostaglandins..Dev Biol2006;289:263-72

[40] Xie WL,Robertson DL,Simmons DL.Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing..Proc Natl Acad Sci U S A1991;88:2692-6 PMCID:PMC51304

[41] Yokoyama C,Tanabe T.Primary structure of sheep prostaglandin endoperoxide synthase deduced from cDNA sequence..FEBS Lett1988;231:347-51

[42] Snipes JA,Shelness GS,Busija DW.Cloning and characterization of cyclooxygenase-1b (putative cyclooxygenase-3) in rat..J Pharmacol Exp Ther2005;313:668-76

[43] Adegboyega PA.Immunohistochemical expression of cyclooxygenase-2 in normal kidneys..Appl Immunohistochem Mol Morphol2004;12:71-4

[44] Kirschenbaum A,Yao S,Klausner AP.Immunohistochemical localization of cyclooxygenase-1 and cyclooxygenase-2 in the human fetal and adult male reproductive tracts..J Clin Endocrinol Metab2000;85:3436-41

[45] FitzGerald GA.COX-2 and beyond: approaches to prostaglandin inhibition in human disease..Nat Rev Drug Discov2003;2:879-90

[46] Hashemi Goradel N,Salehi E,Mortezaee K.Cyclooxygenase-2 in cancer: a review..J Cell Physiol2018;

[47] Yang H.Cyclooxygenase-2 in synaptic signaling..Curr Pharm Des2008;14:1443-51 PMCID:PMC2561288

[48] Stasinopoulos I,Bhujwalla ZM.Inflammation, but not hypoxia, mediated HIF-1alpha activation depends on COX-2..Cancer Biol Ther2009;8:31-5 PMCID:PMC3058789

[49] Black SA,Gurule NJ,Lyons TR.Semaphorin 7a exerts pleiotropic effects to promote breast tumor progression..Oncogene2016;35:5170-8 PMCID:PMC5720143

[50] Cerny J,Horejsi V.Noncovalent associations of T lymphocyte surface proteins..Eur J Immunol1996;26:2335-43

[51] Walzer T,Comeau MR.Plexin C1 engagement on mouse dendritic cells by viral semaphorin A39R induces actin cytoskeleton rearrangement and inhibits integrin-mediated adhesion and chemokine-induced migration..J Immunol2005;174:51-9

[52] Scott GA,Fricke AF.Plexin C1, a receptor for semaphorin 7a, inactivates cofilin and is a potential tumor suppressor for melanoma progression..J Invest Dermatol2009;129:954-63

[53] Wang W,Condeelis J.The cofilin pathway in breast cancer invasion and metastasis..Nat Rev Cancer2007;7:429-40 PMCID:PMC4270061

[54] Ono S.Mechanism of depolymerization and severing of actin filaments and its significance in cytoskeletal dynamics..Int Rev Cytol2007;258:1-82

[55] Pasterkamp RJ,Spriggs MK.Semaphorin 7A promotes axon outgrowth through integrins and MAPKs..Nature2003;424:398-405

[56] Scott GA,Fricke AF.Semaphorin 7a promotes spreading and dendricity in human melanocytes through beta1-integrins..J Invest Dermatol2008;128:151-61

[57] Elder AM,Crump LS,Wessells VM.Semaphorin 7A promotes macrophage-mediated lymphatic remodeling during postpartum mammary gland involution and in breast cancer..Cancer Res2018;78:6473-85 PMCID:PMC6239927

[58] Ma B,Lee CG,Lee CM.Role of chitinase 3-like-1 and semaphorin 7a in pulmonary melanoma metastasis..Cancer Res2015;75:487-96 PMCID:PMC4321965

[59] Hanahan D.The hallmarks of cancer..Cell2000;100:57-70

[60] Ichim G.A fate worse than death: apoptosis as an oncogenic process..Nat Rev Cancer2016;16:539-48

[61] Al-Dimassi S,El-Sibai M.Cancer cell resistance mechanisms: a mini review..Clin Transl Oncol2014;16:511-6

[62] Vachon PH.Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation..J Signal Transduct2011;2011:738137 PMCID:PMC3139189

[63] Kim YN,Sung JY,Kim H.Anoikis resistance: an essential prerequisite for tumor metastasis..Int J Cell Biol2012;2012:306879 PMCID:PMC3296207

[64] Lund LR,Thomasset N,Pyke C.Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways..Development1996;122:181-93 PMCID:PMC2933211

[65] Schere-Levy C,Quaglino A,Cirio MC.Leukemia inhibitory factor induces apoptosis of the mammary epithelial cells and participates in mouse mammary gland involution..Exp Cell Res2003;282:35-47

[66] Hughes K.The multifaceted role of STAT3 in mammary gland involution and breast cancer..Int J Mol Sci2018;19:E1695 PMCID:PMC6032292

[67] Castillo-Lluva S,Blanco-Gomez A,Garcia-Cenador B.A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development..Oncogene2015;34:4777-90 PMCID:PMC4560637

[68] Sakamoto K,Yoo KH,Rajbhandari N.Janus kinase 1 is essential for inflammatory cytokine signaling and mammary gland remodeling..Mol Cell Biol2016;36:1673-90 PMCID:PMC4959311

[69] Sargeant TJ,Resemann HK,Skepper J.Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization..Nature cell biology2014;16:1057-68 PMCID:PMC4216597

[70] Segatto I,Belletti B.STAT3 in breast cancer onset and progression: a matter of time and context..Int J Mol Sci2018;19:E2818 PMCID:PMC6163512

[71] Yu H,Jove R.STATs in cancer inflammation and immunity: a leading role for STAT3..Nat Rev Cancer2009;9:798-809 PMCID:PMC4856025

[72] Akhtar N,Mironov A.Rac1 controls both the secretory function of the mammary gland and its remodeling for successive gestations..Developmental Cell2016;38:522-35 PMCID:PMC5022528

[73] Watson CJ.Involution: apoptosis and tissue remodelling that convert the mammary gland from milk factory to a quiescent organ..Breast Cancer Res2006;8:203 PMCID:PMC1557708

[74] Green KA.ECM degrading proteases and tissue remodelling in the mammary gland..Bioessays2005;27:894-903

[75] Hojilla CV,Khokha R.TIMP3 regulates mammary epithelial apoptosis with immune cell recruitment through differential TNF dependence..PLoS One2011;6:e26718 PMCID:PMC3203873

[76] Hanayama R.Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8..Proc Natl Acad Sci U S A2005;102:16886-91 PMCID:PMC1277971

[77] Schorr K,Bar-Peled U,Heredia A.Gain of Bcl-2 is more potent than bax loss in regulating mammary epithelial cell survival in vivo..Cancer Res1999;59:2541-5

[78] Walton KD,Rucker EB3rd,Miyoshi K.Conditional deletion of the bcl-x gene from mouse mammary epithelium results in accelerated apoptosis during involution but does not compromise cell function during lactation..Mech Dev2001;109:281-93

[79] Schwertfeger KL,Anderson SM.Mammary gland involution is delayed by activated Akt in transgenic mice..Mol Endocrinol2001;15:867-81

[80] Radisky DC.Mammary involution and breast cancer risk: transgenic models and clinical studies..J Mammary Gland Biol Neoplasia2009;14:181-91 PMCID:PMC2693781

[81] Li M,Robinson G,Wagner KU.Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution..Proc Natl Acad Sci U S A1997;94:3425-30 PMCID:PMC20386

[82] Clarkson RW,Lee J,Watson CJ.Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression..Breast Cancer Res2004;6:R92-109 PMCID:PMC400653

[83] Fornetti J,Betts CB,Jindal S.Mammary gland involution as an immunotherapeutic target for postpartum breast cancer..J Mammary Gland Biol Neoplasia2014;19:213-28 PMCID:PMC4363120

[84] Acerbi I,Dean I,Au A.Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration..Integr Biol (Camb)2015;7:1120-34 PMCID:PMC4593730

[85] Li F,Chen J,Roop DR.Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration..Sci Signal2010;3:ra13 PMCID:PMC2905599

[86] Huang Q,Liu X,Shi W.Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy..Nat Med2011;17:860-6 PMCID:PMC3132290

[87] Hanahan D.Hallmarks of cancer: the next generation..Cell2011;144:646-74

[88] Nature reviews Cancer. The tumor microenvironment. Available from: https://www.nature.com/collections/khylqkxqbr/content/reviews. [Last accessed on 1 Feb 2019]

[89] Provenzano PP,Eliceiri KW.Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage..Oncogene2009;28:4326-43 PMCID:PMC2795025

[90] McDaniel SM,Biroc SL,Singh M.Remodeling of the mammary microenvironment after lactation promotes breast tumor cell metastasis..Am J Pathol2006;168:608-20 PMCID:PMC1606507

[91] Bemis LT.Reproductive state of rat mammary gland stroma modulates human breast cancer cell migration and invasion..Cancer Res2000;60:3414-8

[92] O’Brien J,Barkan D,Schedin P.Non-steroidal anti-inflammatory drugs target the pro-tumorigenic extracellular matrix of the postpartum mammary gland..Int J Dev Biol2011;55:745-55

[93] Clarke R.Stromelysin-1 promotes mammary carcinogenesis..Breast Cancer Res1999;1:66605

[94] Paszek MJ,Johnson KR,Rozenberg GI.Tensional homeostasis and the malignant phenotype..Cancer Cell2005;8:241-54

[95] Walker RA.The complexities of breast cancer desmoplasia..Breast Cancer Res2001;3:143-5 PMCID:PMC138677

[96] Kreike B,Horlings H,Peterse H.Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas..Breast Cancer Res2007;9:R65 PMCID:PMC2242660

[97] Provenzano PP,Campbell JM,White JG.Collagen reorganization at the tumor-stromal interface facilitates local invasion..BMC Med2006;4:38 PMCID:PMC1781458

[98] Qiuchen G,Nathan P,Pepper S.Mammary gland involution provides a unique model to study the TGF-beta cancer paradox..J Clin Med2017;6:10 PMCID:PMC5294963

[99] Nguyen AV.Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution..Development2000;127:3107-18

[100] Imamura T,Inoue Y.The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis..Breast Cancer2012;19:118-24

[101] Meng XM,Lan HY.TGF-beta: the master regulator of fibrosis..Nat Rev Nephrol2016;12:325-38

[102] Kang HR,Homer RJ.Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis..J Exp Med2007;204:1083-93 PMCID:PMC2118575

[103] Gan Y,Peng X,Chen Q.Role of semaphorin 7a signaling in transforming growth factor β1-induced lung fibrosis and scleroderma-related interstitial lung disease..Arthritis Rheum2011;63:2484-94 PMCID:PMC3651701

[104] Reilkoff RA,Murray LA,Russell T.Semaphorin 7a+ regulatory T cells are associated with progressive idiopathic pulmonary fibrosis and are implicated in transforming growth factor-β1-induced pulmonary fibrosis..Am J Respir Crit Care Med2013;187:180-8 PMCID:PMC3570653

[105] Esnault S,Johansson MW,Han ST.Semaphorin 7A is expressed on airway eosinophils and upregulated by IL-5 family cytokines..Clin Immunol2014;150:90-100 PMCID:PMC3947215

[106] De Minicis S,Agostinelli L,Trozzi L.Semaphorin 7A contributes to TGF-β-mediated liver fibrogenesis..Am J Pathol2013;183:820-30 PMCID:PMC5819760

[107] Kopp MA,Gatzemeier N,Pruss H.Spinal cord injury induces differential expression of the profibrotic semaphorin 7A in the developing and mature glial scar..Glia2010;58:1748-56

[108] Lee Y,Dai F,Scher JK.Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment..Clin Exp Nephrol2018;22:906-16

[109] Esnault S,Bernau K,Kelly EA.Endogenous semaphorin-7A impedes human lung fibroblast differentiation..PLoS One2017;12:e0170207 PMCID:PMC5240965

[110] Hynes RO.Integrins: bidirectional, allosteric signaling machines..Cell2002;110:673-87

[111] Barkan D,Michalowski AM,Chu I.Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment..Cancer Res2010;70:5706-16 PMCID:PMC3436125

[112] Eke I.Focal adhesion signaling and therapy resistance in cancer..Semin Cancer Biol2015;31:65-75

[113] Jiang WG,Katoh M,Gieseler F.Tissue invasion and metastasis: molecular, biological and clinical perspectives..Semin Cancer Biol.2015;35 Suppl:S244-S75

[114] Narunsky L,Bochner F.Imaging aspects of the tumor stroma with therapeutic implications..Pharmacol Ther2014;141:192-208 PMCID:PMC3947248

[115] Seguin L,Weis SM.Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance..Trends Cell Biol2015;25:234-40 PMCID:PMC4380531

[116] Guo W.Integrin signalling during tumour progression..Nat Rev Mol Cell Biol2004;5:816-26

[117] Hamidi H.Every step of the way: integrins in cancer progression and metastasis..Nat Rev Cancer2018;18:533-48

[118] Humphries JD,Humphries MJ.Integrin ligands at a glance..J Cell Sci2006;119:3901-3 PMCID:PMC3380273

[119] Liu H,Shim AH,Chen X.Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1..Cell2010;142:749-61 PMCID:PMC2936782

[120] Jongbloets BC,Schellino R,Parkash J.Stage-specific functions of semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors..Nat Commun2017;8:14666 PMCID:PMC5353663

[121] Suzuki K,Yamamoto M,Takegahara N.Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin..Nature2007;446:680-4

[122] Naci D,Aoudjit F.Alpha2beta1 integrin in cancer development and chemoresistance..Semin Cancer Biol2015;35:145-53

[123] Broom OJ,Sjolander A.Alpha2beta1 integrin signalling enhances cyclooxygenase-2 expression in intestinal epithelial cells..J Cell Physiol2006;209:950-8

[124] Esquivel-Velazquez M,Palacios-Arreola MI,Castro JI.The role of cytokines in breast cancer development and progression..J Interferon Cytokine Res2015;35:1-16 PMCID:PMC4291218

[125] Vannini F,Nath N.The dual role of iNOS in cancer..Redox Biol2015;6:334-43 PMCID:PMC4565017

[126] Martinez FO.The M1 and M2 paradigm of macrophage activation: time for reassessment..F1000Prime Rep2014;6:13 PMCID:PMC3944738

[127] Chen Y,Wang Q.Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein..J Hematol Oncol2017;10:36 PMCID:PMC5286803

[128] Qian BZ.Macrophage diversity enhances tumor progression and metastasis..Cell2010;141:39-51 PMCID:PMC4994190

[129] Vasiliadou I.The role of macrophages in bone metastasis..J Bone Oncol2013;2:158-66 PMCID:PMC4723381

[130] Wyckoff JB,Lin EY,Goswami S.Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors..Cancer Res2007;67:2649-56

[131] Lin EY,Russell RG.Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy..J Exp Med2001;193:727-40 PMCID:PMC2193412

[132] Monks J,Geske FJ,Hanson L.Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release..Cell Death Differ2005;12:107-14

[133] Monks J,Kruk ER,Henson PM.Epithelial cells remove apoptotic epithelial cells during post-lactation involution of the mouse mammary gland..Biol Reprod2008;78:586-94

[134] O’Brien J,Durand-Rougely C.Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution..Development2012;139:269-75

[135] Harney AS,Entenberg D,Guo P.Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA..Cancer Discov2015;5:932-43 PMCID:PMC4560669

[136] Holmes S,Fosberry A,Michalovich D.Sema7A is a potent monocyte stimulator..Scand J Immunol2002;56:270-5

[137] Hugo HJ,Ramsay RG.New insights on COX-2 in chronic inflammation driving breast cancer growth and metastasis..J Mammary Gland Biol Neoplasia2015;20:109-19

[138] Gan L,Huang J,Huang H.Cyclooxygenase-2 in tumor-associated macrophages promotes metastatic potential of breast cancer cells through Akt pathway..Int J Biol Sci2016;12:1533-43 PMCID:PMC5166494

[139] Esbona K,Saha S,Van Doorn RR.The presence of cyclooxygenase 2, tumor-associated macrophages, and collagen alignment as prognostic markers for invasive breast carcinoma patients..Am J Pathol2018;188:559-73 PMCID:PMC5963475

[140] Ingman WV,Gouon-Evans V,Pollard JW.Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland..Dev Dyn2006;235:3222-9

[141] Muthukkaruppan VR,Auerbach R.Tumor-induced neovascularization in the mouse eye..J Natl Cancer Inst1982;69:699-708

[142] Holmgren L,Folkman J.Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression..Nat Med1995;1:149-53

[143] Parangi S,Christofori G,Grosfeld J.Antiangiogenic therapy of transgenic mice impairs de novo tumor growth..Proc Natl Acad Sci U S A1996;93:2002-7 PMCID:PMC39899

[144] Ramirez RA,Schedin P,Masso-Welch PA.Alterations in mast cell frequency and relationship to angiogenesis in the rat mammary gland during windows of physiologic tissue remodeling..Dev Dyn2012;241:890-900 PMCID:PMC3979934

[145] Pepper MS,Mandriota SJ,Oikemus S.Regulation of VEGF and VEGF receptor expression in the rodent mammary gland during pregnancy, lactation, and involution..Dev Dyn2000;218:507-24

[146] Chan TR,Li Y.Collagen-gelatin mixtures as wound model, and substrates for VEGF-mimetic peptide binding and endothelial cell activation..Acta Biomater2015;15:164-72 PMCID:PMC4404521

[147] Bordeleau F,Lollis EM,Zanotelli MR.Matrix stiffening promotes a tumor vasculature phenotype..Proc Natl Acad Sci U S A2017;114:492-7 PMCID:PMC5255592

[148] Samani A,Plewes D.Elastic moduli of normal and pathological human breast tissues: an inversion-technique-based investigation of 169 samples..Phys Med Biol2007;52:1565-76

[149] Fang M,Peng C.Collagen as a double-edged sword in tumor progression..Tumour Biol2014;35:2871-82 PMCID:PMC3980040

[150] Masson N.HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels..J Cell Sci2003;116:3041-9

[151] Takeda N,Imai Y,Kawanami D.Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1..Circ Res2004;95:146-53

[152] Kaidi A,Williams AC.Direct transcriptional up-regulation of cyclooxygenase-2 by hypoxia-inducible factor (HIF)-1 promotes colorectal tumor cell survival and enhances HIF-1 transcriptional activity during hypoxia..Cancer Res2006;66:6683-91

[153] Greenhough A,Moore AE,Williams AC.The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment..Carcinogenesis2009;30:377-86

[154] Jones MK,Peskar BM,Itani RM.Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing..Nat Med1999;5:1418-23

[155] Morote-Garcia JC,Kohler D.Endothelial semaphorin 7A promotes neutrophil migration during hypoxia..Proc Natl Acad Sci U S A2012;109:14146-51 PMCID:PMC3435204

[156] Zhang M,Dong M,Jin F.Endothelial semaphorin 7A promotes inflammation in seawater aspiration-induced acute lung injury..Int J Mol Sci2014;15:19650-61 PMCID:PMC4264131

[157] He M.Expression of hypoxia-induced semaphorin 7A correlates with the severity of inflammation and osteoclastogenesis in experimentally induced periapical lesions..Arch Oral Biol2017;75:114-9

[158] Garcia-Areas R,Amat S,Carrio R.Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice..Front Physiol2014;5:17 PMCID:PMC3914020

[159] Ghanem RC,Rojas J,Kim DJ.Semaphorin 7A promotes angiogenesis in an experimental corneal neovascularization model..Curr Eye Res2011;36:989-96 PMCID:PMC3709026

[160] Foskett AM,Trzeciakowski JP,Muthuchamy M.Hypoxia and extracellular matrix proteins influence angiogenesis and lymphangiogenesis in mouse embryoid bodies..Front Physiol2011;2:103 PMCID:PMC3243103

[161] Swartz MA.Immunomodulatory roles of lymphatic vessels in cancer progression..Cancer Immunol Res2014;2:701-7

[162] Hosono K,Kawakami T,Majima M.Signaling of prostaglandin E receptors, EP3 and EP4 facilitates wound healing and lymphangiogenesis with enhanced recruitment of M2 macrophages in mice..PLoS One2016;11:e0162532 PMCID:PMC5053515

[163] Zeng C,Yang Z.The close correlation between heparanase and COX-2 expression in lymphangiogenesis of cervical cancer..Med Oncol2014;31:314

[164] Iwata C,Komuro A,Kiyono K.Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis..Cancer Res2007;67:10181-9

[165] Lala PK,Majumder M.Roles of prostaglandins in tumor-associated lymphangiogenesis with special reference to breast cancer..Cancer Metastasis Rev2018;37:369-84

[166] Gyorffy B,Eklund AC,Budczies J.An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients..Breast Cancer Res Treat2010;123:725-31

[167] Burke CA,Berger MF,Essex MN.Children’s international polyposis (CHIP) study: a randomized, double-blind, placebo-controlled study of celecoxib in children with familial adenomatous polyposis..Clin Exp Gastroenterol2017;10:177-85 PMCID:PMC5525455

[168] Steinbach G,Phillips RK,Hawk E.The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis..N Engl J Med2000;342:1946-52