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Mohamedi et al. J Cancer Metastasis Treat 2019;5:37 I http://dx.doi.org/10.20517/2394-4722.2018.81 Page 13 of 15

It is noteworthy that fibulin-1 expression was initially associated with improved survival in patients with
[48]
a lymphoid infiltrate at the tumor site . Similarly, the Kaplan-Meier analysis showed better prognosis for
patients with high levels of fibulin-1 than for those with low fibulin-1 expression. In fact, the low expression
of fibulin-1 has been described in various tumor types, such as gastric cancer, bladder cancer, colorectal
cancer and hepatocellular carcinoma. In all these cases, low expression correlates with the hypermethylation
of the FBLN1 promoter and can be used as a prognosis marker [30-33,49] . Thus, our data are in accordance
with all these studies in which it seems feasible that the presence of fibulin-1 might have a prevalent anti-
tumor activity. In our immunohistochemical analysis, we could detect the presence of only fibulin-1; no
ADAMTS-1 was observed. From our cellular experiments, it is clear that the presence of both proteins has
a pronounced effect on the tumorigenic properties of both cell lines. The downregulation of ADAMTS-1
might be a mechanism of escape towards tumor progression, avoiding binding with fibulin-1 and thus
eliminating the anti-tumoral properties of their interaction.

In summary, the interactions between members of both families of ECM proteins, fibulins and ADAMTSs,
seem to be important for cancer development, as is the case for ADAMTS-12/fibulin-2 and ADAMTS-1/
fibulin-1. Furthermore, we have also been able to demonstrate the cleavage of fibulin-2 by ADAMTS-4 and
[50]
ADAMTS-5, which increased the tumorigenic potential of breast cancer cell lines . Therefore, it is tempting
to speculate the existence of similar mechanisms that control fibulin-1 participation in breast cancer
development and its interaction with other ECM components, a hypothesis that warrant further study.

DECLARATIONS
Acknowledgments
We also thank the IUOPA units of “Banco de tumores” and “ Histopatología molecular en modelos animales
en cancer”.

Authors’ contributions
Made substantial contributions to the conception and design of the study and performed data analysis and
interpretation: Mohamedi Y, Fontanil T, Cal S, Obaya AJ
Performed data acquisition: Cobo T, Cobo JL
Provided technical support: García-Suárez O
Provided administrative support and performed histological interpretation: Vega JA, Cobo J
Wrote the manuscript: Mohamedi Y, Cal S, Obaya AJ

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by the Instituto Asturiano de Odontología (IAO). Mohamedi Y is recipient of a
fellowship from the FICYT, “Fundación para el Fomento en Asturias de la Investigación Científica Aplicada
y la Tecnología” (“Severo Ochoa” Research Program, Principado de Asturias), and Tania Fontanil is recipient
of a contract from the “Departamento de Investigación de Clínica Órdoñez (Oviedo)”.

Conflicts of interest
All authors declared that there are not conflicts of interest.

Ethical approval and consent to participate
The study methodologies conformed to the standards set by the Declaration of Helsinki and were approved
by the Ethics Committee of Clinical Investigation of the Hospital Universitario de Asturias (HUCA).