Abstract
Suppressive effects of extracellular matrix (ECM) upon various cancers have been reported. Glioblastoma multiforme has poor prognosis and new therapies are desired. This work investigated the effects of a saline-soluble fraction of urinary bladder ECM (ECM-SF) upon glioma cells. Viability at 24 hours in 1, 5, or 10 mg/mL ECM-SF-spiked media was evaluated in primary glioma cells (0319, 1015, 1119), glioma cell lines (A172, T98G, U87MG, C6), and brain cell lines (HCN-2, HMC3). Viability universally decreased at 5 and 10 mg/mL with U87MG, HCN-2, and HCM3 being least sensitive. Apoptosis in 0319 and 1119 cells was confirmed via NucView 488. Bi-weekly intravenous injection of ECM-SF (120 mg/kg) for 10 weeks in Sprague-Dawley rats did not affect weight, temperature, complete blood count, or multi-organ histology (N = 5). Intratumoral injection of ECM-SF (10 uL of 30 mg/mL) at weeks 2–4 post C6 inoculation in Wistar rats increased median survival from 24.5 to 51 days (hazard ratio for death 0.22) and decreased average tumor volume at time of death from 349 mm3 to 90 mm3 over 10 weeks (N = 6). Mass spectrometry identified 2,562 protein species in ECM-SF, parent ECM, and originating tissue. These results demonstrate the suppressive effects of ECM on glioma and warrant further study.
Highlights
The extracellular matrix (ECM) represents a major portion of the tissue microenvironment and is composed of functional and structural molecules such as cytokines, growth factors, proteoglycans, collagens, and matrix-bound nanovesicles, among others [1–3]
Viability at 24 hours in 1, 5, or 10 mg/mL ECM harvested from non-neoplastic porcine urinary bladder (ECM-SF)-spiked media was evaluated in primary glioma cells (0319, 1015, 1119), glioma cell lines (A172, T98G, U87MG, C6), and brain cell lines (HCN-2, HMC3)
Mass spectrometry identified 2,562 protein species in ECM-SF, parent ECM, and originating tissue. These results demonstrate the suppressive effects of ECM on glioma and warrant further study
Summary
The extracellular matrix (ECM) represents a major portion of the tissue microenvironment and is composed of functional and structural molecules such as cytokines, growth factors, proteoglycans, collagens, and matrix-bound nanovesicles, among others [1–3]. The tissue organization field theory (TOFT) supposes that metaplastic and neoplastic transformation of cells is directly related to changes in the microenvironment/ECM [6, 7]. If this theory is accurate, manipulation of the tumor microenvironment could modulate neoplastic cell behavior or survival. Several studies have documented the effects of mammalian non-neoplastic ECM upon neoplastic cells in vitro and in vivo. These studies have included several www.oncotarget.com types of cancer including breast, urinary bladder, prostate, colon, skin, and esophageal, among others [8–15]. A study by the same group found increased apoptosis in one metaplastic and two neoplastic cell lines exposed to urinary ladder matrix ECM [13]
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