TNF antagonists may offer therapeutic potential in solid tumors, but patients who have high serum levels of TNF-a fail to respond to infliximab, suggesting consumption of the circulating antibody and loss of transmembrane TNF-a (tmTNF-a) on tumors by ectodomain shedding. Addressing this possibility, we developed a monoclonal antibody (mAb) that binds both full-length tmTNF-a and its N-terminal truncated fragment on the membrane after tmTNF-a processing but does not cross-react with soluble TNF-a. We documented high levels of tmTNF-a expression in primary breast cancers, lower levels in atypical hyperplasia or hyperplasia, but undetectable levels in normal breast tissue, consistent with the notion that tmTNF-a is a potential therapeutic target. Evaluations in vitro and in vivo further supported this assertion. tmTNF-a mAb triggered antibodydependent cell-mediated cytotoxicity against tmTNF-a-expressing cells but not to tmTNF-a-negative cells. In tumor-bearing mice, tmTNF-a mAb delayed tumor growth, eliciting complete tumor regressions in some mice. Moreover, tmTNF-a mAb inhibited metastasis and expression of CD44v6, a prometastatic molecule. However, the antibody did not activate tmTNF-a-mediated reverse signaling, which facilitates tumor survival and resistance to apoptosis, but instead inhibited NF-kB activation and Bcl-2 expression by decreasing tmTNF-a-positive cells. Overall, our results established that tmTNF-a mAb exerts effective antitumor activities and offers a promising candidate to treat tmTNF-a-positive tumors, particularly in patients that are nonresponders to TNF antagonists. Cancer Res; 73(13); 4061-74. Ó2013 AACR.
Understanding how autocrine/paracrine factors regulate neural stem cell (NSC) survival and growth is fundamental to the utilization of these cells for therapeutic applications and as cellular models for the brain. In vitro, NSCs can be propagated along with neural progenitors (NPs) as neurospheres (nsphs). The nsph conditioned medium (nsph-CM) contains cell-secreted factors that can regulate NSC behavior. However, the identity and exact function of these factors within the nsph-CM has remained elusive. We analyzed the nsph-CM by mass spectrometry and identified DSD-1-proteoglycan, a chondroitin sulfate proteoglycan (CSPG), apolipoprotein E (ApoE) and cystatin C as components of the nsph-CM. Using clonal assays we show that CSPG and ApoE are responsible for the ability of the nsph-CM to stimulate nsph formation whereas cystatin C is not involved. Clonal nsphs generated in the presence of CSPG show more than four-fold increase in NSCs. Thus CSPG specifically enhances the survival of NSCs. CSPG also stimulates the survival of embryonic stem cell (ESC)-derived NSCs, and thus may be involved in the developmental transition of ESCs to NSCs. In addition to its role in NSC survival, CSPG maintains the three dimensional structure of nsphs. Lastly, CSPG's effects on NSC survival may be mediated by enhanced signaling via EGFR, JAK/STAT3 and PI3K/Akt pathways.
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