Abstract
Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (p<0.001) and tW (p<0.0001). There was no difference in tV or tW end of study vs. before injections in p75KD/LLC+TNF group. In 3 other groups tV and tW were increased 2.7-4.5-fold (p<0.01, p<0.0002 and p<0.0001). Pathological examination revealed that 1/3 of p75KD/LLC+rmTNF tumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics.
Highlights
Despite recent advances in the treatment of lung malignancies, lung cancer is still the most common cause of cancer-related deaths in humans [1,2]
All 30 animals developed comparable size flank tumors by day 7 and there was no difference in the tumor volumes between intact Lewis lung carcinoma 1 (LLC) vs. p75KD/LLC (242 6 34.9 mm3 vs. 263 6 29.9 mm3, respectively, P = NS)
Starting on day 8 post-inoculation tumor volumes were measured daily in the morning followed by intra-tumoral injections of either saline or recombinant murine TNF (rmTNF) (12.5 ng/g of mouse weight) twice a day for 6 days
Summary
Despite recent advances in the treatment of lung malignancies, lung cancer is still the most common cause of cancer-related deaths in humans [1,2]. Standard treatments for these tumors advanced, the five year survival after diagnosis remains low. TNF induces its effects by binding two distinct receptors, TNFR1/p55 and TNFR2/p75 [5,6]. Due to significant differences in the cytoplasmic domain, it has been postulated that TNF receptors trigger distinct signaling pathways upon interaction with the ligand TNF [8]. In agreement with this concept, activation of the caspases cascade and subsequent induction of apoptosis by TNF is an exclusive feature of p55 activation through signaling via a well-defined death domain, which is absent in p75 receptor signaling [9,10]. Few specific signaling pathways of p75 have been elucidated, especially within the context of tumorigenesis and endothelial cell (ECs) biology [11–13]
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