Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastases?

Abstract

The majority of cancer deaths can be attributed to cancer cell metastases that migrate to distant target organs. Brain metastases constitute one of the leading causes of morbidity and mortality among cancer patients, occurring in about 40% of patients with metastatic disease. Thus, there exists an unmet need for early detection, diagnosis, and treatment directed against early stage cancer cell metastasis. Previous studies have reported the development of methods to detect and identify early circulating tumor cells (CTCs) in the bloodstream prior to their seeding into distant organs. Using a comprehensive analysis of total CTCs mRNA content, investigators have developed a mRNA “transcriptome signature” of 126 genes involved in CTC metastatic events. The genes were parsed into various metastatic-related activities indicating that CTCs sustained a semi-dormancy state bent on: (1) stress survival; (2) metabolic maintenance; (3) DNA and translational stability; and (4) chemotactic pro-inflammatory capabilities. These activities suggested that CTCs might be susceptible to interactions with protein-derived peptide segments whose actions are involved with metastatic activities such as cell invasiveness, contact, adhesion, motility, spreading, and migration. The use of protein-derived (encrypted) peptides to impede CTC metabolic activities and disrupt signaling pathways could have therapeutic potential in patients with early metastatic disease.

Keywords

Breast cancer / brain / metastasis / peptides / plasma proteins / tumor cells / circulation / transcriptome

References

[1] Lin X.Treatment of brain metastases..J Clin Oncol2015;33:3475-84 PMCID:PMC5087313

[2] Stewart BW,editors.World Cancer Report 2014..2014;Lyon, FranceInternational Agency for Research on Cancer1-20

[3] Cooper JB,Tobias ME,Hillard V,Gandhi CD,Jhanwar-Uniyal M.Molecular sequence of events and signaling pathways in cerebral metastases..Anticancer Res2018;38:1859-77

[4] Rack B,Juckstock J,Hepp P,Friedl TW,Tesch H,Fehm T,Lichtenegger W,Friese K,Janni W.Circulating tumor cells predict survival in early average-to-high risk breast cancer patients..J Natl Cancer Inst2014;106:1-30 PMCID:PMC4112925

[5] Rhim AD,Aiello NM,Bailey JM,Reichert M,Rustgi AK,Leach SD.EMT and dissemination precede pancreatic tumor formation..Cell2012;148:349-61 PMCID:PMC3266542

[6] Meng S,Frenkel EP,Naftalis EZ,Beitsch PD,Hoover S,Haley B,Fleming TP,Terstappen LW,Tucker TF,Wang J.Circulating tumor cells in patients with breast cancer dormancy..Clin Cancer Res2004;10:8152-62

[7] Tsao MN.Brain metastases: advances over the decades..Ann Palliat Med2015;4:225-32

[8] Welch HG,Albertsen PC.Trends in metastatic breast and prostate cancer--lessons in cancer dynamics..N Engl J Med2015;373:1685-7

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

[10] Boral D,Liu HN,Sprouse ML,Hong DS,Thiery JP,Marchetti D.Molecular characterization of breast cancer CTCs associated with brain metastasis..Nat Commun2017;8:196-204 PMCID:PMC5543046

[11] Yu M,Wittner BS,Smas ME,Isakoff SJ,Wells MN,Concannon KF,Sequist LV,Sgroi D,Ramaswamy S,Haber DA.Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition..Science2013;339:580-4 PMCID:PMC3760262

[12] Hyun KA,Han H,Choi W,Jung HI.Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer..Oncotarget2016;7:24677-87 PMCID:PMC5029733

[13] Jordan NV,Wittner BS,Ligorio M,Yu M,Licausi JA,O'Keefe RM,Boukhali M,Onozato ML,Kapur R,Ting DT,Ramaswamy S,Maheswaran S.HER2 expression identifies dynamic functional states within circulating breast cancer cells..Nature2016;537:102-6 PMCID:PMC5161614

[14] Valiente M,Jin X,Zhang XH,Chaft JE,Huse JT,Massague J.Serpins promote cancer cell survival and vascular co-option in brain metastasis..Cell2014;156:1002-16 PMCID:PMC3988473

[15] Alix-Panabieres C.Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy..Cancer Discov2016;6:479-91

[16] Ingham KC,Erickson HP.Localization of a cryptic binding site for tenascin on fibronectin..J Biol Chem2004;279:28132-5

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

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

[19] Pike SE,Jones KD,Appella E,Nakhasi H,Wirth P,Tosato G.Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth..J Exp Med1998;188:2349-56 PMCID:PMC2212424

[20] Kamphaus GD,Panka DJ,Ramchandran R,Maeshima Y,Sukhatme VP.Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth..J Biol Chem2000;275:1209-15

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

[22] Uversky VN,Narizhneva NV,Tomashevski A.Structural properties of alpha-fetoprotein from human cord serum: the protein molecule at low pH possesses all the properties of the molten globule..FEBS Lett1995;364:165-7

[23] Mizejewski GJ,Hauer CR,Gierthy J.Alpha-fetoprotein derived synthetic peptides: assay of an estrogen-modifying regulatory segment..Mol Cell Endocrinol1996;118:15-23

[24] Mizejewski G,Butterstein G.Review and proposed action of alpha-fetoprotein growth inhibitory peptides as estrogen and cytoskeletal-associated factors..Cell Biol Int2004;28:913-33

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

[26] Jin J,Zou L,Li S,Zhang P,Xiao F.AFP mRNA level in enriched circulating tumor cells from hepatocellular carcinoma patient blood samples is a pivotal predictive marker for metastasis..Cancer Lett2016;378:33-7

[27] Mizejewski GJ.Third domain ligand binding fragment of alpha-fetoprotein: detection of metastasis-associated molecular targets..Cancer Therapy Oncol Int J2017;6:1-15

[28] Valiente M,Jin X,Zhang XH,Chaft JE,Huse JT,Massague J.Serpins promote cancer cell survival and vascular co-option in brain metastasis..Cell2014;156:1002-16 PMCID:PMC3988473

[29] 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

[30] Atemezem A,Marfaing R,Pontet M,Charnaux N.Human alpha-fetoprotein binds to primary macrophages..Biochem Biophys Res Commun2002;296:507-14

[31] Mizejewski GJ.Alpha-fetoprotein as a biomarker for immunodeficiency diseases: relevance to ataxia telangiectasia & related disorders..J Immunodefic Disor2014;3:1-12

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

[33] Mizejewski GJ.Role of integrins in cancer: survey of expression patterns..Proc Soc Exp Biol Med1999;222:124-38

[34] Muehlemann M,Dauphinee M.Review of growth inhibitory peptide as a biotherapeutic agent for tumor growth, adhesion, and metastasis..Cancer Metastasis Rev2005;24:441-67

[35] Mizejewski GJ,Garnuszek P,Cohen BD,Posypanova GA,Severin ES.Targeted delivery of anti-cancer growth inhibitory peptides derived from human alpha-fetoprotein: review of an International Multi-Center Collaborative Study..J Drug Target2010;18:575-88

[36] Czokalo M.Alpha fetoprotein inhibits aggregation of human platelets..Haematologia (Budap)1989;22:11-8

[37] Hua SC,Lu CH,Yu HI,PT,Chang TC.The effects of growth inhibitory peptide on follicular thyroid cancer cell growth, migration, and invasion..Tumori2010;96:448-51