Abstract
The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate.
Highlights
Cell motility is a key prerequisite for cancer cell invasiveness and metastatic spread, and has become the focus of many research efforts aiming to identify the mechanisms empowering cell transformation from a stationary to migratory state
The present study demonstrates the multifunctional role of hrRNASET2 in numerous processes integral to tumor survival and spread, rendering it a unique agent with a projected high therapeutic potential
These observations are believed to underlie its significant dose-dependent inhibitory effect on cell motility as well as the protein's marked impact on both angiogenin-triggered human umbilical vascular endothelial cells (HUVEC) tube formation and pollen tube growth. These effects were further manifested in tumor xenograft models of the aggressive human A375SM melanoma and CT29 colon cancer cell lines, in which all tested hrRNASET2 regimens inhibited subcutaneous colon cancer and melanoma tumor growth and reduced tumor blood vessel counts and areas, inhibiting melanoma cancer cell metastatic spread to the lung and significantly extending survival times
Summary
Cell motility is a key prerequisite for cancer cell invasiveness and metastatic spread, and has become the focus of many research efforts aiming to identify the mechanisms empowering cell transformation from a stationary to migratory state. Actin cytoskeleton reorganization has been pinned as a key element underlying cell motility and invasion [1] and presents an attractive target in antitumorigenic and antimetastatic agent design. Relapse and poor prognosis correlate with elevated circulating levels of angiogenic factors and overall metastatic potential and patient outcome can be predicted by microvessel density [2, 3]. In particular, feature distinct angiogenic processes, which have been shown to rapidly enhance their aggressiveness and progression [5]. Many therapeutic approaches aim to achieve tumor regression or dormancy by targeting angiogenic factors and regulators. Combined treatments or administration of agents that target multiple pathways underlying tumor progression will inevitably display enhanced antitumor potency
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