Beth Lewis

Surgery-induced tumor growth acceleration and synchronous metastatic growth promotion have been observed for decades. Surgery-induced wound healing, orchestrated through growth factors, chemokines, and cytokines, can negatively impact patients harboring residual or metastatic disease. We provide detailed clinical evidence of this process in surgical breast, prostate, and colorectal cancer patients. Plasma samples were analyzed from 68 cancer patients who had not received treatment before surgery or adjuvant therapy until at least four weeks post-surgery. The levels of plasma cytokines, chemokines, and growth factors were simultaneously quantified and profiled using multiplexed immunoassays for eight time points sampled per patient. The immunologic processes are induced immediately after surgery in patients, characterized by a drastic short-term shift in the expression levels of pro-inflammatory and angiogenic molecules and cytokines. A rapid and significant spike in circulating plasma levels of hepatocyte growth factor (HGF), interleukin-6 (IL-6), placental growth factor (PLGF), and matrix metalloproteinase-9 (MMP-9) after surgery was noted. The rise in these molecules was concomitant with a significant drop in transforming growth factor-β1 (TGF-β1), platelet-derived growth factor (PDGF-AB/BB), insulin-like growth factor-1 (IGF-1), and monocyte chemoattractant protein-2 (MCP-2). If not earlier, each plasma analyte was normalized to baseline levels within 1–2 weeks after surgery, suggesting that surgical intervention alone was responsible for these effects. The effects of surgical tumor removal on disrupting the pro-inflammatory and angiogenic plasma profiles of cancer patients provide evidence for potentiating malignant progression. Our findings indicate a narrow therapeutic window of opportunity after surgery to prevent disease recurrence.

We discovered a novel therapeutic target critical for SARS-CoV-2, cellular infectivity and the induction of the cytokine release syndrome. Here, we show that the mammalian enzyme neuraminidase-1 (Neu-1) is part of a highly conserved signaling platform that regulates the dimerization and activation of the ACE2 receptors and the Toll-like receptors (TLRs) implicated in the cytokine release syndrome (CRS). Activated Neu-1 cleaves glycosylated residues that provide a steric hindrance to both ACE2 and TLR dimerization, a process critical to both viral attachment to the receptor and entry into the cell and TLR activation. Blocking Neu-1 inhibited ACE2 receptor dimerization and internalization, TLR dimerization and activation, and the expression of several key inflammatory molecules implicated in the CRS and death from ARDS. Treatments that target Neu-1 are predicted to be highly effective against infection with SARS-CoV-2, given the central role played by this enzyme in viral cellular entry and the induction of the CRS.