Oncotarget | Inhibition of fibroblast secreted QSOX1 perturbs extracellular matrix in the tumor microenvironment and decreases tumor growth and metastasis in murine cancer models


Oncotarget Volume 11, Issue 4: Extracellular matrix plays an important role in tumor development and dissemination, but few points of therapeutic intervention targeting ECM of the tumor microenvironment have been exploited to date.

Based on this finding and the increased QSOX1 expression in the stroma of aggressive breast carcinomas, we developed monoclonal antibody inhibitors with the aim of preventing QSOX1 from participating in pro-metastatic ECM remodeling.

Here the authors show that QSOX1 inhibitory antibodies decreased tumor growth and metastasis in murine cancer models and had added benefits when provided together with chemotherapy.

Dr. Deborah Fass and Dr. Tal Ilani from the Department of Structural Biology at the Weizmann Institute of Science in Rehovot Israel said in their Oncotarget article "Tumor-induced remodelling of genetically normal adjacent tissues offers opportunities for the development of novel anti-cancer strategies."

Aberrant expression of laminin, another key ECM component, is also observed in many cancers and may contribute to regulation of cancer stem cells, cell invasion, angiogenesis, and drug resistance.

Figure 1: QSOX1 production by tumor-associated fibroblasts.

Figure 1: QSOX1 production by tumor-associated fibroblasts. (A) Parallel cultures of sub-confluent WI-38 fibroblasts were either treated with TGF-β (+) or left untreated (–), and the amount of QSOX1 in the medium after 48 hours was quantified by western blot. Error bars are standard error from four biological replicates (p-value < 0.01). (B) Primary fibroblast cultures derived from biopsy of a lung cancer patient were evaluated for QSOX1 transcript levels and secreted QSOX1 protein. CAF and NF cultures were grown with or without conditioned medium from a tumor cell line prior to mRNA quantification and protein analysis by western blot. The two QSOX1 bands, indicated by arrowheads, arise from the two QSOX1 splice variants, as observed previously [5]. Error bars are standard deviation from three parallel cultures. (C) A breast tumor biopsy was IHC stained for QSOX1. Intense QSOX1 staining is seen within the tumors, and arrows indicate highly stained fibroblasts in the tumor vicinity.

In particular, disulfide bond formation in the ECM of fibroblast cells is required for assembling a matrix capable of supporting tumor cell adhesion and migration.

They observed that inhibition of QSOX1 during fibroblast growth prevented formation of the copious pro-migratory ECM deposited by these cells, resulting in a failure of tumor cells to penetrate the fibroblast layer.

QSOX1 modifies ECM extracellularly, so excess QSOX1 produced by cancer-associated stromal fibroblasts in a physiological context is expected to be accessible for blocking by antibodies administered systemically.

Consistent findings were observed in multiple independent experiments, and an investigation of the mechanistic basis for QSOX1 inhibitory antibody in vivo extends previous observations made using cell culture mimetics of tumor-stromal interactions.

The Fass/Ilani Research Team concluded in their Oncotarget paper, "we provide the first evidence that inhibition of QSOX1 with a specific inhibitory antibody affects tumor growth and metastasis in vivo."

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Full text - https://doi.org/10.18632/oncotarget.27438

Correspondence to - Deborah Fass - [email protected] and Tal Ilani - [email protected]

Keywords - monoclonal antibody inhibitor, tumor microenvironment, fibroblasts, extracellular matrix remodeling, disulfide bonds

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