TLR9 ligation in pancreatic stellate cells promotes tumorigenesis.

Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.

Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways.

Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1(-/-) mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS)-mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF) expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis.

The unintended effects of a boxed warning.

OBJECTIVE: To demonstrate a real-life correlation that after the US Food and Drug Administration introduced a boxed warning concerning malignancies to the labeling for topical calcineurin inhibitors, reluctance to use topical calcineurin inhibitors has led to their substitution with other therapies that have their own risks. PARTICIPANTS: An anonymous survey of attendees of the 2007 Fall Clinical Dermatology conference in Las Vegas, Nevada, from October 17-19, 2007. More than 95 percent of attendees were dermatologists; a small number of mid-level practitioners attended as well. Of nearly 700 attendees, the first 504 who agreed to complete the survey were included. RESULTS: More than 40 percent of dermatologists surveyed claimed that more than 20 percent of their atopic dermatitis patients are not adequately controlled since the introduction of the boxed warning. Forty-eight percent claim that more than 20 percent of those patients were adequately controlled with topical calcineurin inhibitors as part of their regimens. Eighty percent of dermatologists surveyed agree that more than 10 precent of those patients were adequately controlled with topical calcineurin inhibitors in their regimens. CONCLUSION: While caution is usually prudent, the introduction of a boxed warning in the case of topical calcineurin inhibitors has led to the use of treatments that often have greater risks than the topical calcineurin inhibitors that they replaced.