Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2016

Open Access 01-12-2016 | Research

Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients

Authors: Dana Hamam, Mohamed Abdouh, Zu-Hua Gao, Vincenzo Arena, Manuel Arena, Goffredo Orazio Arena

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2016

Login to get access

Abstract

Background

It was reported that metastases might occur via transfer of biologically active blood circulating molecules from the primary tumor to distant organs rather than only migration of cancer cells. We showed in an earlier study that exposure of immortalized human embryonic kidney cells (HEK 293) to cancer patient sera, induce their transformation into undifferentiated cancers due to a horizontal transfer of malignant traits. In the present work, we tested the hypothesis that even other human cells as long as they are deficient for a single oncosuppressor gene might undergo malignant transformation when exposed to human cancer serum.

Methods

We used the CRISPR/Cas9 system to establish a stable BRCA1 knockout (KO) in human fibroblasts. The BRCA1-KO fibroblasts were exposed to cancer patients’ sera or healthy patients’ sera for 2 weeks. Treated cells were analyzed for cell proliferation and transformation to study their susceptibility to the oncogenic potential of cancer patients’ sera and to determine the possible mechanisms underlying their hypothesized transformation.

Results

BRCA1-KO fibroblasts treated with cancer patients’ sera displayed higher proliferation and underwent malignant transformation as opposed to wild type control fibroblasts, which were not affected by exposure to cancer patients’ sera. The malignant transformation was not seen when BRCA1-KO fibroblasts were treated with healthy human sera. Histological analysis of tumors generated by BRCA1-KO fibroblasts showed that they were carcinomas with phenotypical characteristics related to the cancers of the blood donor patients. Interestingly, BRCA1-KO fibroblasts were significantly more prone to internalize serum-derived exosomes, when compared to wild type fibroblasts. This suggests that oncosuppressor genes might protect the integrity of the cell genome also by blocking integration of cancer-derived exosomes.

Conclusion

These data support the hypothesis that any human cells carrying a single oncosuppressor mutation is capable of integrating cancer factors carried in the blood and undergo complete malignant transformation. Oncosuppressor genes might protect the cell genome by impeding the integration inside the cells of these mutating factors.
Appendix
Available only for authorised users
Literature
1.
2.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed
3.
Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ specific colonization. Nat Rev Cancer. 2009;9:274–84.CrossRefPubMed
4.
Skog J, Wurdinger T, van Rijn S. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10:1470–81.CrossRefPubMedPubMedCentral
5.
Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011;71:3792–801.CrossRefPubMed
6.
Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 2011;71(15):5346–56.CrossRefPubMed
7.
Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D. Melanoma exosomes educate bone marrow progenitor cells toward a prometastatic phenotype through MET. Nat Med. 2012;18:883–91.CrossRefPubMedPubMedCentral
8.
Abdel-Mageed ZY, Yang Y, Thomas R, Ranjan M, Mondal D, Moraz K, Fang Z, Rezk BM, Moparty K, Sikka SC, Sartor O, Abdel-Mageed AB. Neoplastic reprogramming of patient-derived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells. 2014;32:983–97.CrossRefPubMedPubMedCentral
9.
Fujita Y, Yoshioka Y, Ochiya T. Extracellular vesicle transfer of cancer pathogenic components. Cancer Sci. 2016. [DOI: 10.1111Epub ahead of print].
10.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.CrossRefPubMed
11.
Runz S, Keller S, Rupp C, Stoeck A, Issa Y, Koensgen D. Malignant ascites-derived exosomes of ovarian carcinoma patients contain CD24 and EpCAM. Gynecol Oncol. 2007;107:563–71.CrossRefPubMed
12.
Pisetsky DS, Gauley J, Ullal AJ. Microparticles as a source of extracellular DNA. Immunol Res. 2010;49:227–34.CrossRef
13.
Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, De Medina P, Monsarrat B, Perret B, Silvente-Poirot S, Poirot M, Record M. Exosomes account for vesicle mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res. 2010;51:2105–20.CrossRefPubMedPubMedCentral
14.
Gaiffe E, Pretet JL, Launay S, Jacquin L, Saunier M, Hetzel G. Apoptotic HPV positive cancer cells exhibit transforming properties. PLoS One. 2012;7:e36766.CrossRefPubMedPubMedCentral
15.
Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun. 2011;2:180.CrossRefPubMedPubMedCentral
16.
Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta. 2007;1775(1):181–232.PubMed
17.
Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.PubMed
18.
19.
Candelario KM, Steindler DA. The role of extracellular vesicles in the progression of neurodegenerative disease and cancer. Trends Mol Med. 2014;20(7):368–74.CrossRefPubMedPubMedCentral
20.
Pant S, Hilton H, Burczynski ME. The multifaceted exosome: biogenesis, role in normal and aberrant cellular function, and frontiers for pharmacological and biomarker oppertunities. Biochem Pharmacol. 2012;83(11):1484–94.CrossRefPubMed
21.
Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.CrossRefPubMed
22.
23.
Garcıa-Olmo D, Garcıa-Olmo DC, Ontanon J, Martinez E, Vallejo M. Tumor DNA circulating in the plasma might play a role in metastasis. The hypothesis of the genometastasis. Histol Histopathol. 1999;14:1159–64.PubMed
24.
García-Olmo DC, Domínguez C, García-Arranz M, Anker P, Stroun M, García-Verdugo JM, García-Olmo D. Cell-free nucleic acids circulating in the plasma of colorectal cancer patients induce the oncogenic transformation of susceptible cultured cells. Cancer Res. 2010;70:560–7.CrossRefPubMed
25.
Trejo-Becerril C, Perez-Cardenas E, Taja-Chayeb L, Anker P, Herrera-Goepfert R, Medina-Velazquez LA, Hidalgo-Miranda A, Perez-Montiel D, Chavez-Blanco A, Cruz-Velazquez J, Dıaz-Chavez J, Gaxiola M, as-Gonzalez AD. Cancer Progression Mediated by Horizontal Gene Transfer in an In Vivo Model. PLoS One. 2012;7(12):e52754.CrossRefPubMedPubMedCentral
26.
Abdouh M, Zhou S, Arena V, Arena M, Lazaris A, Onerheim R, Metrakos P, Arena G. Transfer of malignant trait to immortalized human cells following exposure to human cancer serum. J Exp Clin Cancer Res. 2014;33(1):86.CrossRefPubMedPubMedCentral
27.
Gudmundsdottir K, Ashworth A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene. 2006;25(43):5864–74.CrossRefPubMed
28.
Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001;10(7):31–42.CrossRef
29.
Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: New genetic developments, new therapeutic avenues. Hum Genet. 2008;124(1):31–42.CrossRefPubMed
30.
Pal T, Permuth-Wey J, Betts JA. BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer. 2005;104(12):2807–16.CrossRefPubMed
31.
32.
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic MM. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35.CrossRefPubMed
33.
Polanska UM, Orimo A. Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J Cell Physiol. 2013;228(8):1651–7.CrossRefPubMed
34.
Paulsson J, Micke P. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin Cancer Biol. 2014;25:61–8.CrossRefPubMed
35.
Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.CrossRefPubMed
36.
Suzuki M, Tanin D. Gene expression profiling of human lynph node metastases and matched primary breast carcinomas: clinical implications. Mol Oncol. 2007;1(2):172–80.CrossRefPubMed
37.
Huang S, Chen Y, Podsypanina K, Li Y. Comparison of expression profiles of metastatic versus primary mammary tumors in MMTV-Wnt-1 and MMTV-Neu transgenic mice. Neoplasia. 2008;10(2):118–24.CrossRefPubMedPubMedCentral
38.
39.
Yoshida A, Okamoto N, Tozawa-Ono A, KoizUmi H, Kiguchi K, Ishizuka B, Kumai T, Suzuki N. Proteomic analysis of differential protein expression by brain metastases of gynecological malignancies. Hum Cell. 2013;26(2):56–66.CrossRefPubMedPubMedCentral
40.
41.
Jiang Q, Greenberg RA. Deciphering the BRCA1 tumor suppressor network. J Biol Chem. 2015;290(29):17724–32.CrossRefPubMed
42.
Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, Diaz Jr LA, Goodman SN, David KA, Juhl H, Kinzler KW, Vogelstein B. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102(45):16368–73.CrossRefPubMedPubMedCentral
43.
Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem. 2014;289(7):3869–75.CrossRefPubMedPubMedCentral
Metadata
Title
Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients
Authors
Dana Hamam
Mohamed Abdouh
Zu-Hua Gao
Vincenzo Arena
Manuel Arena
Goffredo Orazio Arena
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2016
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-016-0360-9

Other articles of this Issue 1/2016

Journal of Experimental & Clinical Cancer Research 1/2016 Go to the issue

Research

Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases

Research

Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

Research

Tripartite motif containing 62 is a novel prognostic marker and suppresses tumor metastasis via c-Jun/Slug signaling-mediated epithelial-mesenchymal transition in cervical cancer

Research

Heregulin-1ß and HER3 in hepatocellular carcinoma: status and regulation by insulin

Erratum

Erratum to: Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting

Research

Long noncoding RNA NEAT1 promotes laryngeal squamous cell cancer through regulating miR-107/CDK6 pathway
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits