Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb 2;24(3):2929.
doi: 10.3390/ijms24032929.

The Association of Integrins β3, β4, and αVβ5 on Exosomes, CTCs and Tumor Cells with Localization of Distant Metastasis in Breast Cancer Patients

Evgeniya S Grigoryeva  1   2 , Luibov A Tashireva  1   3 , Olga E Savelieva  3   4 , Marina V Zavyalova  3 , Nataliya O Popova  5 , Gleb A Kuznetsov  3 , Elena S Andryuhova  3 , Vladimir M Perelmuter  3
Affiliations

The Association of Integrins β3, β4, and αVβ5 on Exosomes, CTCs and Tumor Cells with Localization of Distant Metastasis in Breast Cancer Patients

Evgeniya S Grigoryeva et al. Int J Mol Sci. .

Abstract

Integrins are cell adhesion receptors, which play a role in breast cancer invasion, angiogenesis, and metastasis. Moreover, it has been shown that exosomal integrins provide organotropic metastasis in a mouse model. In our study, we aimed to investigate the expression of integrins β3, β4, and αVβ5 on exosomes and tumor cells (circulating tumor cells and primary tumor) and their association with the localization of distant metastasis. We confirmed the association of exosomal integrin β4 with lung metastasis in breast cancer patients. However, we were unable to evaluate the role of integrin β3 in brain metastasis due to the rarity of this localization. We established no association of exosomal integrin αVβ5 with liver metastasis in our cohort of breast cancer patients. The further evaluation of β3, β4, and αVβ5 integrin expression on CTCs revealed an association of integrin β4 and αVβ5 with liver, but not the lung metastases. Integrin β4 in the primary tumor was associated with liver metastasis. Furthermore, an in-depth analysis of phenotypic characteristics of β4+ tumor cells revealed a significantly increased proportion of E-cadherin+ and CD44+CD24- cells in patients with liver metastases compared to patients with lung or no distant metastases.

Keywords: breast cancer; circulating tumor cells; exosomes; integrin; metastasis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) A representative image of microvesicles isolated from the plasma of a breast cancer patient: ovals show exosomes, white arrows show protein aggregates, black arrows show non-vesicles (40–80 nm). The inset in the right angle shows a non-vesicle (20–40 nm) and 2, 3 represent exosomes, while 4 represents large vesicles (100–200 nm). (B) Intrapersonal variants of exosomal integrins co-expression in each breast cancer patient. (C) Proportions of exosomes co-expressed β3, β4, and αVβ5 integrins in breast cancer patients with metastasis in different organs. Samples were tested for statistical outliers, then one-way ANOVA was used to compare the means of independent groups.
Figure 2
Figure 2
(A) Number of CTC co-expressed β3, β4, and αVβ5 integrins in breast cancer patients. (B) Number of CTC co-expressed β3, β4, and αVβ5 integrins in breast cancer patients with distant metastases in different organs. (C) Intrapersonal variants of integrins co-expression in CTCs of each breast cancer patient. Samples were tested for statistical outliers, then one-way ANOVA was used to compare the means of independent groups.
Figure 3
Figure 3
(A) Proportion of tumor cells expressed β4 integrin in breast cancer patients with distant metastases in different organs. (B) Proportion of integrin β4+ tumor cells with EMT features in breast cancer patients with distant metastases in different organs. (C) Proportion of integrin β4+ tumor cells with stemness features in breast cancer patients with distant metastases in different organs. (D,E) EMT (E-cadherin and N-cadherin) and stem (CD44+CD24- and ALDH1) markers in Integrin beta 4-positive tumor cells in breast cancer patients (Multiplex IHC, (A)—magnification 630×, (B)—magnification 400×). Samples were tested for statistical outliers, then one-way ANOVA was used to compare the means of independent groups.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Huang R., Rofstad E.K. Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma. J. Exp. Clin. Cancer Res. 2018;37:92. doi: 10.1186/s13046-018-0763-x. - DOI - PMC - PubMed
    1. Hoshino A., Costa-Silva B., Shen T.L., Rodrigues G., Hashimoto A., Mark M.T., Molina H., Kohsaka S., Di Giannatale A., Ceder S., et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–335. doi: 10.1038/nature15756. - DOI - PMC - PubMed
    1. Othman N., Jamal R., Abu N. Cancer-Derived Exosomes as Effectors of Key Inflammation-Related Players. Front. Immunol. 2019;10:2103. doi: 10.3389/fimmu.2019.02103. - DOI - PMC - PubMed
    1. Desgrosellier J.S., Barnes L.A., Shields D.J., Huang M., Lau S.K., Prévost N., Tarin D., Shattil S.J., Cheresh D.A. An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression. Nat. Med. 2009;15:1163–1169. doi: 10.1038/nm.2009. - DOI - PMC - PubMed
    1. Sloan E.K., Pouliot N., Stanley K.L., Chia J., Moseley J.M., Hards D.K., Anderson R.L. Tumor-specific expression of αVβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Res. 2006;8:R20. doi: 10.1186/bcr1398. - DOI - PMC - PubMed