Surgical stress promotes the development of cancer metastases by a coagulation-dependent mechanism involving natural killer cells in a murine model.

OBJECTIVE: To determine whether the postoperative hypercoagulable state is responsible for the increase in metastases observed after surgery. BACKGROUND: Surgery precipitates a hypercoagulable state and increases the formation of cancer metastases in animal models. Coagulation promotes metastases by facilitating the formation of microthrombi around tumor cell emboli (TCE), thereby inhibiting natural killer (NK) cell-mediated destruction. METHODS: Mice underwent surgery preceded by tumor cell inoculation to establish pulmonary metastases in the presence or absence of various perioperative anticoagulants. Pulmonary TCE were quantified and characterized using fluorescently labeled fibrinogen and platelets. The role of NK cells was evaluated by repeating these experiments after antibody depletion in a genetically deficient strain and by adoptively transferring NK cells into NK-deficient mice. RESULTS: Surgery resulted in a consistent and significant increase in metastases while a number of different anticoagulants and platelet depletion attenuated this effect. Impaired clearance of TCE from the lungs associated with an increase in peritumoral fibrin and platelet clot formation was observed in surgically stressed mice, but not in control mice or mice that received perioperative anticoagulation. The increase in TCE survival conferred by surgery and inhibited by perioperative anticoagulation was eliminated by the immunological or genetic depletion of NK cells. Adoptive transfer experiment confirms that surgery impairs NK cell function. CONCLUSIONS: Surgery promotes the formation of fibrin and platelet clots around TCE, thereby impairing NK cell-mediated tumor cell clearance, whereas perioperative anticoagulation attenuates this effect. Therapeutic interventions aimed at reducing peritumoral clot formation and enhancing NK cell function in the perioperative period will have important clinical implications in attenuating metastatic disease after cancer surgery.

ORFV: a novel oncolytic and immune stimulating parapoxvirus therapeutic.

Replicating viruses for the treatment of cancer have a number of advantages over traditional therapeutic modalities. They are highly targeted, self-amplifying, and have the added potential to act as both gene-therapy delivery vehicles and oncolytic agents. Parapoxvirus ovis or Orf virus (ORFV) is the prototypic species of the Parapoxvirus genus, causing a benign disease in its natural ungulate host. ORFV possesses a number of unique properties that make it an ideal viral backbone for the development of a cancer therapeutic: it is safe in humans, has the ability to cause repeat infections even in the presence of antibody, and it induces a potent T(h)-1-dominated immune response. Here, we show that live replicating ORFV induces an antitumor immune response in multiple syngeneic mouse models of cancer that is mediated largely by the potent activation of both cytokine-secreting, and tumoricidal natural killer (NK) cells. We have also highlighted the clinical potential of the virus by demonstration of human cancer cell oncolysis including efficacy in an A549 xenograft model of cancer.

CEACAM1 is a direct SOX10 target and inhibits melanoma immune infiltration and stemness.

SOX10 is a key regulator of melanoma progression and promotes a melanocytic/differentiated state. Here we identified melanoma cell lines lacking SOX10 expression which retain their in vivo growth capabilities. More importantly, we find that SOX10 can regulate T-cell infiltration in melanoma while also decreasing common cancer stem cell (CSC) properties. We show that SOX10 regulates CEACAM1, a surface protein with immunomodulatory properties. SOX10 directly binds to a distal CEACAM1 promoter region approximately 3-4kbps from the CEACAM1 transcriptional start site. Furthermore, we show that a SOX10-CEACAM1 axis can suppress CD8+ T-cell infiltration as well as reduce CSC pool within tumors, leading to reduced tumor growth. Overall, these results identify SOX10 as a direct regulator of CEACAM1, and uncover both a pro- and anti-tumorigenic roles for SOX10 in melanoma.

Loss of the Ste20-like kinase induces a basal/stem-like phenotype in HER2-positive breast cancers.

HER2 is overexpressed in 20-30% of all breast cancers and is associated with an invasive disease and poor clinical outcome. The Ste20-like kinase (SLK) is activated downstream of HER2/Neu and is required for efficient epithelial-to-mesenchymal transition, cell cycle progression, and migration in the mammary epithelium. Here we show that loss of SLK in a murine model of HER2/Neu-positive breast cancers significantly accelerates tumor onset and decreases overall survival. Transcriptional profiling of SLK knockout HER2/Neu-derived tumor cells revealed a strong induction in the triple-negative breast cancer marker, Sox10, accompanied by an increase in mammary stem/progenitor activity. Similarly, we demonstrate that SLK and Sox10 expression are inversely correlated in patient samples, with the loss of SLK and acquisition of Sox10 marking the triple-negative subtype. Furthermore, pharmacological inhibition of AKT reduces SLK-null tumor growth in vivo and is rescued by ectopic Sox10 expression, suggesting that Sox10 is a critical regulator of tumor growth downstream of SLK/AKT. These findings highlight a role for SLK in negatively regulating HER2-induced mammary tumorigenesis and provide mechanistic insight into the regulation of Sox10 expression in breast cancer.