nsc-74859 and Carcinogenesis

Purpose To (a) identify key expressed genes in the periablational rim after radiofrequency ablation (RFA) and their role in driving the stimulation of distant tumor growth and (b) use adjuvant drug therapies to block key identified mediator(s) to suppress off-target tumorigenic effects of hepatic RFA. Materials and Methods This institutional animal care and use committee-approved study was performed in C57BL6 mice (n = 20) and F344 rats (n = 124). First, gene expression analysis was performed in mice after hepatic RFA or sham procedure; mice were sacrificed 24 hours to 7 days after treatment. Data were analyzed for differentially expressed genes (greater than twofold change) and their functional annotations. Next, animals were allocated to hepatic RFA or sham treatment with or without STAT3 (signal transducer and activator of transcription 3) inhibitor S3I-201 for periablational phosphorylated STAT3 immunohistochemistry analysis at 24 hours. Finally, animals with subcutaneous R3230 adenocarcinoma tumors were allocated to RFA or sham treatment with or without a STAT3 inhibitor (S3I-201 or micellar curcumin, eight arms). Outcomes included distant tumor growth, proliferation (Ki-67 percentage), and microvascular density. Results At 24 hours, 217 genes had altered expression (107 upregulated and 110 downregulated), decreasing to 55 genes (27 upregulated and 28 downregulated) and 18 genes (four upregulated, 14 downregulated) at 72 hours and 7 days, respectively. At 24 hours, STAT3 occurred in four of seven activated pathways associated with pro-oncogenic genes at network analysis. Immunohistochemistry analysis confirmed elevated periablational phosphorylated STAT3 24 hours after RFA, which was suppressed with S3I-201 (percentage of positive cells per field: 31.7% ± 3.4 vs 3.8% ± 1.7; P < .001). Combined RFA plus S3I-201 reduced systemic distant tumor growth at 7 days (end diameter: 11.8 mm ± 0.5 with RFA plus S3I-201, 19.8 mm ± 0.7 with RFA alone, and 15 mm ± 0.7 with sham procedure; P < .001). STAT3 inhibition with micellar curcumin also suppressed postablation stimulation of distant tumor growth, proliferation, and microvascular density (P < .01). Conclusion Gene expression analysis identified multiple pathways upregulated in the periablational rim after hepatic RFA, of which STAT3 was active in four of seven. Postablation STAT3 activation is linked to increased distant tumor stimulation and can be suppressed with adjuvant STAT3 inhibitors.

Topics: Adenocarcinoma; Aminosalicylic Acids; Animals; Benzenesulfonates; Carcinogenesis; Catheter Ablation; Cell Transformation, Neoplastic; Chemotherapy, Adjuvant; Disease Models, Animal; Down-Regulation; Female; Gene Expression; Liver Neoplasms, Experimental; Mammary Neoplasms, Experimental; Mice, Inbred C57BL; Microvessels; Neoplasm Metastasis; Neoplasm Transplantation; Oncogene Proteins; Phosphorylation; Rats, Inbred F344; Skin Neoplasms; STAT3 Transcription Factor; Up-Regulation

Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (Thrb(PV/PV)Pten(+/-) mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. WT and Thrb(PV/PV)Pten(+/-) mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition (EMT). S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase 4 (CDK4), CDK6, and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated Thrb(PV/PV)Pten(+/-) mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated Thrb(PV/PV)Pten(+/-) mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of EMT. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer.

Topics: Aminosalicylic Acids; Animals; Benzenesulfonates; Carcinogenesis; Cell Proliferation; Diet, High-Fat; Disease Models, Animal; Down-Regulation; Epithelial-Mesenchymal Transition; Mice; Mice, Transgenic; Obesity; PTEN Phosphohydrolase; STAT3 Transcription Factor; Thyroid Gland; Thyroid Hormone Receptors beta; Thyroid Neoplasms

We investigated whether exposing a wound-healing-sensitive cell line to human wound fluid (HWF) could prime the cells to increase their tumor-forming ability in nude mice and, if so, whether this ability can be inhibited by pharmacological substances.. Experimental animal model.. Take rate was measured in BALB/c nude mice after pretreatment of the cells with HWF using human serum and fetal bovine serum as controls. Inhibition of signal transducer and activator of transcription 3 (STAT3) with S3I-201 tocilizumab, and of interleukin 6 receptor (IL6R) with tocilizumab was performed.. Preincubation with HWF resulted in a significant increase in take rate compared to controls. The increase in take rate could be decreased by both STAT3 and IL6R inhibition.. The results indicate that head and neck squamous cell cancer cells might be stimulated to increase their tumor-forming ability both close to a surgical wound and at more distant locations, as a consequence of the wound-healing response. The work also suggests new treatment modalities aimed at decreasing these stimulatory effects.. NA Laryngoscope, 126:E213-E217, 2016.

Topics: Aminosalicylic Acids; Animals; Antibodies, Monoclonal, Humanized; Benzenesulfonates; Carcinogenesis; Cell Line, Tumor; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred BALB C; Receptors, Interleukin-6; STAT3 Transcription Factor; Wound Healing