Breast cancer, metastasis, and the microenvironment: disabling the tumor cell-to-stroma communication network

Abstract

Breast cancer (BC) is the leading cause of cancer-related deaths in women worldwide. However, the majority of cancer mortalities can be attributed to cancer cell metastasis to distal organs/tissues rather than the primary tumor mass itself. The microenvironment surrounding the main tumor mass, as well as its final migration destination, plays a crucial role in the survival, growth, proliferation, and progression of BC. Intercellular stromal cells and components of the microenvironment surrounding a tumor comprise a nurturing cubicle that provides a communication network of cross-talk and signaling between the tumor cells and the extracellular matrix (ECM) and interstitial cells. This network connection enables the tumor cells to engage in metastatic-associated activities such as cell adhesion, invasiveness, mobility, migration, cell shape change, cell-to-cell contact, and basement membrane degradation. An untapped therapeutic approach that might disable the communication network between cancer and stromal cells could possibly aid in providing this unmet need in treating metastatic disease. The intravenous administration of select protein-derived peptides to patients might have the potential to occupy, saturate, and block receptors and binding proteins at the interstitial/ECM communication interface with tumors.

Keywords

Alpha-fetoprotein / cancer / metastasis / breast / microenvironment / interstitium / extra-cellular matrix / stroma

References

[1] Siegel R,Zou Z.Cancer statistics..CA Cancer J Clin2014;64:9-29

[2] Tran-Thanh D.The role of stromal factors in breast tumorigenicity..Am J Pathol2010;176:1072-74 PMCID:PMC2832127

[3] Amicone L.Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma..Transl Gastroenterol Hepatol2018;3:24 PMCID:PMC6002256

[4] Liu Q,Jiang X,Liu Z.Factors involved in cancer metastasis: a better understanding to “seed and soil” hypothesis..Mol Cancer2017;16:176 PMCID:PMC5712107

[5] Nieto MA,Jackson RA.Emt: 2016..Cell2016;166:21-45

[6] Mukherjee D.The role of chemokine receptor CXCR4 in breast cancer metastasis..Am J Cancer Res2013;3:46-57 PMCID:PMC3555200

[7] Gupta GP.Cancer metastasis: building a framework..Cell2006;127:679-95

[8] Minciacchi VR,Di Vizio D.Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes..Semin Cell Dev Biol2015;40:41-51 PMCID:PMC4747631

[9] Peinado H,Lyden D.The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts..Semin Cancer Biol2011;21:139-46

[10] Cavallaro S.CXCR4/CXCL12 in non-small-cell lung cancer metastasis to the brain..Int J Mol Sci2013;14:1713-27 PMCID:PMC3565343

[11] Mizejewski GJ.Breast cancer, chemokines, and metastases: a search for decoy ligands of the CXCR4 receptor..J Neoplasms2018;1:1-9

[12] Tran-Thanh D.The role of stromal factors in breast tumorigenicity..Am J Pathol2010;176:1072-4 PMCID:PMC2832127

[13] Scala S.Molecular Pathways: Targeting the CXCR4-CXCL12 axis--untapped potential in the tumor microenvironment..Clin Cancer Res2015;21:4278-85

[14] Angst BD,Magee AI.The cadherin superfamily: diversity in form and function..J Cell Sci2001;114:629-41

[15] Hulpiau P.Molecular evolution of the cadherin superfamily..Int J Biochem Cell Biol2009;41:349-69

[16] Mizejewski GJ.The third domain ligand binding fragment of alpha-fetoprotein: detection of metastasis-associated molecular targets..2017;6:1-15

[17] Newman PJ.Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology..Arterioscler Thromb Vasc Biol2003;23:953-64

[18] Nagase H.Matrix metalloproteinases..J Biol Chem1999;274:21491-4

[19] Zhu P,Xu R,Zhao J.The interaction between ADAM 22 and 14-3-3zeta: regulation of cell adhesion and spreading..Biochem Biophys Res Commun2003;301:991-999

[20] Collier IE,Goldberg GI.On the structure and chromosome location of the 72- and 92-kDa human type IV collagenase genes..Genomics1991;9:429-34

[21] White DJ,Johnson MS.The collagen receptor subfamily of the integrins..Int J Biochem Cell Biol2004;36:1405-10

[22] Hauptmann R,Krystek E,Andree H.Vascular anticoagulant beta: a novel human Ca2+/phospholipid binding protein that inhibits coagulation and phospholipase A2 activity. Its molecular cloning, expression and comparison with VAC-alpha..Eur J Biochem1989;185:63-71

[23] Ornitz DM,Colvin JS,MacArthur CA.Receptor specificity of the fibroblast growth factor family..J Biol Chem1996;271:15292-7

[24] Ohtaki T,Honda S,Hori A.Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor..Nature2001;411:613-7

[25] Lee J,Rice GC,Camerato T.Characterization of two high affinity human interleukin-8 receptors..J Biol Chem1992;267:16283-7

[26] Yamda Y,Wang K,Bell GI.Cloning and functional characteristic of a family of human somatostatin receptors expressed in brain, gastrointestinal tract and kidney..J N Acad Sci (USA)1992;89:251-5 PMCID:PMC48214

[27] Ron D,Chedid M,Cohen OE.Fibroblast growth factor receptor 4 is a high affinity receptor for both acidic and basic fibroblast growth factor but not for keratinocyte growth factor..J Biol Chem1993;268:5388-94

[28] Muller YA,Christinger HW,Cunningham BC.Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site..Proc Natl Acad Sci USA1997;94:7192-7 PMCID:PMC23789

[29] Isobe M,Givol D,Croce CM.Localization of gene for human p53 tumour antigen to band 17p13..Nature1986;320:84-5

[30] Critton DA,Stetson G,Page R.Structural basis of substrate recognition by hematopoietic tyrosine phosphatase..Biochemistry2008;47:13336-45 PMCID:PMC2908255

[31] Muehlemann M,Dauphinee M.Review of growth inhibitory peptide as a biotherapeutic agent for tumor growth, adhesion, and metastasis..Cancer Metastasis Rev2005;24:441-467

[32] Mizejewski GJ.Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastasis?.J Cancer Metastasis Treat2018;4:27

[33] Chiquet-Ehrismann R.Tenascins: regulation and putative functions during pathological stress..J Pathol2003;200:488-99

[34] Cao Y,Davidson D,Marti D.Kringle domains of human angiostatin. Characterization of the anti-proliferative activity on endothelial cells..J Biol Chem1996;271:29461-7

[35] Folkman J.Antiangiogenesis in cancer therapy--endostatin and its mechanisms of action..Exp Cell Res2006;312:594-607

[36] Davenport AP,Dhaun N,Kohan DE.Endothelin..Pharmacol Rev2016;68:357-418 PMCID:PMC4815360

[37] Mizejewski GJ.Alpha-fetoprotein growth inhibitory peptides: potential leads for cancer therapeutics.Mol Cancer Ther2003;2:1243-55

[38] Mizejewski GJ.Survey of functional activities of alpha-fetoprotein derived growth inhibitory peptides: review and prospects..Curr Protein Pept Sci2006;7:73-100

[39] Mizejewski GJ,Dauphinee M.Update of alpha fetoprotein growth-inhibitory peptides as biotherapeutic agents for tumor growth and metastasis..Chemotherapy2006;52:83-90

[40] Mizejewski GJ.The alpha-fetoprotein-derived growth inhibitory peptide 8-mer fragment: review of a novel anticancer agent..Cancer Biother Radiopharm2007;22:73-98

[41] Mizejewski GJ.The alpha-fetoprotein (AFP) third domain: a search for AFP interaction sites of cell cycle proteins..Tumour Biol2016;37:12697-711

[42] Mizejewski GJ.Review of the putative cell-surface receptors for alpha-fetoprotein: identification of a candidate receptor protein family..Tumour Biol2011;32:241-58

[43] Mizejewski GJ.Peptides as receptor ligand drugs and their relationship to G-coupled signal transduction..Expert Opin Investig Drugs2001;10:1063-73

[44] Mizejewski GJ.Mechanism of cancer growth suppression of alpha-fetoprotein derived growth inhibitory peptides (GIP): comparison of GIP-34 versus GIP-8 (AFPep). Updates and Prospects..Cancers (Basel)2011;3:2709-33 PMCID:PMC3757439

[45] Hernandez I,Kedrin D,Zhu L.The EGF/ESF-1 paracrine loop can be triggered by heregulin beta-1 and CXCL 12..Cancer Res2009;69:3221-327 PMCID:PMC2820720