Bo Wook Kim

Nanog signaling in cancer promotes stem-like phenotype and immune evasion

Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.

Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry

BackgroundHypoxia inducible factor-1 alpha (HIF-1α), induced by tumor hypoxia, regulates tumor cell metabolism and metastasis by up-regulation of c-Met, carbonic anhydrase 9 (CA9) and glucose transporter 1 (GLUT1). The prognostic significance of hypoxia and metabolic markers is not clearly defined in cervical cancer. Here, we have examined the primary players in the hypoxia signaling pathway, by immunohistochemistry, but confirming their interactions, as well as defining which proteins are associated with outcome.MethodsThe study subjects were comprised of cervical intraepithelial neoplasia (CIN, n = 209), carcinoma in situ (CIS, n = 74), cervical cancer (n = 179), and matched nonadjacent normal tissues (n = 357). Immunohistochemistry (IHC) was performed to identify HIF-1α, c-Met, CA9, and GLUT1. IHC scoring was performed using automated digital image analysis and the association of hypoxic markers with prognostic outcome was evaluated.ResultsHIF-1α, c-Met, CA9 and GLUT1 expression were higher in cervical cancer than in CIN and normal cervix (all P < 0.001). Among these markers, expression of HIF-1α and c-Met were significantly different in FIGO stage (P < 0.001 and P = 0.019, respectively) and patients with lymph node metastasis (P < 0.001 and P = 0.010, respectively). HIF-1α expression was correlated with c-Met expression in cervical cancer (P < 0.001). High expression of HIF-1α and c-Met showed worse 5-year overall survival rate (P = 0.047 and P = 0.005, respectively) than low expression group, but CA9 and GLUT1 did not show significant survival difference. After adjusting the prognostic covariates, c-Met was found to be an independent risk factor (HR=3.27; 95% CI, 1.05-10.23, P = 0.041) for overall survival in cervical cancer.ConclusionsWe demonstrate that c-Met correlates with HIF-1α and is a poor prognostic factor in survival in cervical cancer.

Autoantibodies against stress-induced phosphoprotein-1 as a novel biomarker candidate for ovarian cancer.

Detection of autoantibodies against tumor‐associated antigens (TAA) has recently been shown to be a powerful tool for early detection of various cancers. The aim of this study was to investigate the possibility of using autoantibodies against TAA as novel biomarkers by a proteomics‐based approach in patients with ovarian cancer. We used two‐dimensional differential gel electrophoresis analysis of immuno‐precipitated tumor antigens (2D‐DITA) to compare the levels of autoandibodies in pretreatment and posttreatment sera of patients with ovarian cancers. The identified autoantibodies were validated by SYBR Green real‐time polymerase chain reaction (PCR) and immunohistochemistry (IHC). We further evaluated the level of autoantibody in sera of 68 ovarian cancer patients by an enzyme‐linked immunosorbent assay (ELISA). The autoantibody directed against stress‐induced phosphoprotein‐1 (STIP‐1) emerged as a novel biomarker candidate for ovarian cancer. SYBR Green PCR and IHC confirmed that the STIP‐1 mRNA and protein expression levels were significantly up‐regulated in ovarian cancers compared with normal and benign tumors (P = 0.003 and P < 0.001, respectively). A preliminary ELISA study showed that the serum levels of anti‐STIP‐1 autoantibodies were significantly elevated in ovarian cancer patients compared with healthy controls (P = 0.03). The results suggest that 2D‐DITA is a useful tool to detect autoantibodies and that STIP‐1 is a potential biomarker candidate for ovarian cancers.

Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer

BackgroundThe apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer.MethodsAPI5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues.ResultsAPI5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.ConclusionsAPI5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.

Pre-treatment diagnosis of endometrial cancer through a combination of CA125 and multiplication of neutrophil and monocyte

Aim:  This study aimed to investigate the clinical value of pre‐treatment leukocyte differential counts and the prediction of endometrial cancer using leukocyte markers.

Human chorionic gonadotrophin regression rate as a predictive factor of postmolar gestational trophoblastic neoplasm in high-risk hydatidiform mole: a case–control study

OBJECTIVE The aim of this study was early prediction of postmolar gestational trophoblastic neoplasm (GTN) after evacuation of high-risk mole, by comparison of human chorionic gonadotrophin (hCG) regression rates. STUDY DESIGN Fifty patients with a high-risk mole initially and spontaneously regressing after molar evacuation were selected from January 1, 1996 to May 31, 2010 (spontaneous regression group). Fifty patients with a high-risk mole initially and progressing to postmolar GTN after molar evacuation were selected (postmolar GTN group). hCG regression rates represented as hCG/initial hCG were compared between the two groups. The sensitivity and specificity of these rates for prediction of postmolar GTN were assessed using receiver operating characteristic curves. Multivariate analyses of associations between risk factors and postmolar GTN progression were performed. RESULTS The mean regression rate of hCG between the two groups was compared. hCG regression rates represented as hCG/initial hCG (%) were 0.36% in the spontaneous regression group and 1.45% in the postmolar GTN group in the second week (p=0.003). Prediction of postmolar GTN by hCG regression rate revealed a sensitivity of 48.0% and specificity of 89.5% with a cut-off value of 0.716% and area under the curve (AUC) of 0.759 in the 2nd week (p<0.001). In patients with an hCG regression rate over 0.716% in the 2nd week, the hazard ratio for progression to postmolar GTN was 3.00 by multivariate analysis (p<0.001). CONCLUSION Differences in hCG regression rates between spontaneous regression and postmolar GTN groups became evident from the second week following molar evacuation. The occurrence of postmolar GTN could be predicted as early as the second week by comparing regression rates. hCG regression rate is easily obtainable and a predictive factor for postmolar GTN.

Synaptonemal Complex Protein 3 Is a Prognostic Marker in Cervical Cancer

Synaptonemal complex protein 3 (SCP3), a member of Cor1 family, is up-regulated in various cancer cells; however, its oncogenic potential and clinical significance has not yet been characterized. In the present study, we investigated the oncogenic role of SCP3 and its relationship with phosphorylated AKT (pAKT) in cervical neoplasias. The functional role of SCP3 expression was investigated by overexpression or knockdown of SCP3 in murine cell line NIH3T3 and human cervical cancer cell lines CUMC6, SiHa, CaSki, and HeLa both in vitro and in vivo. Furthermore, we examined SCP3 expression in tumor specimens from 181 cervical cancer and 400 cervical intraepithelial neoplasia (CIN) patients by immunohistochemistry and analyzed the correlation between SCP3 expression and clinicopathologic factors or survival. Overexpression of SCP3 promoted AKT-mediated tumorigenesis both in vitro and in vivo. Functional studies using NIH3T3 cells demonstrated that the C-terminal region of human SCP3 is important for AKT activation and its oncogenic potential. High expression of SCP3 was significantly associated with tumor stage (P = 0.002) and tumor grade (P<0.001), while SCP3 expression was positively associated with pAKT protein level in cervical neoplasias. Survival times for patients with cervical cancer overexpressing both SCP3 and pAKT (median, 134.0 months, n = 68) were significantly shorter than for patients with low expression of either SCP3 or pAKT (161.5 months, n = 108) as determined by multivariate analysis (P = 0.020). Our findings suggest that SCP3 plays an important role in the progression of cervical cancer through the AKT signaling pathway, supporting the possibility that SCP3 may be a promising novel cancer target for cervical cancer therapy.

Clinical Significance of Serum Anti-human Papillomavirus 16 and 18 Antibodies in Cervical Neoplasia

OBJECTIVE: To estimate the clinical significance of serum anti-human papillomavirus (HPV) antibodies and high-risk cervical HPV DNA in cervical neoplasia. METHODS: The study population comprised patients who were histopathologically diagnosed with cervical intraepithelial neoplasia (CIN) 1 (n=64), CIN 2 and 3 (n=241), cervical cancer (n=170), and normal control participants (n=975). Cervical HPV DNA tests were performed through nucleic acid hybridization assay tests, and serum anti-HPV 16 and 18 antibodies were measured by competitive immunoassay. The associations of HPV DNA and anti-HPV antibodies were evaluated with demographic characteristics and compared according to the levels of disease severity. Anti-HPV antibodies were also investigated with clinicopathologic parameters, including survival data. RESULTS: Among various demographic characteristics, factors involving sexual behavior had a higher tendency of HPV DNA positivity and HPV seropositivity. Human papillomavirus DNA mean titer and positivity were both increased in patients with cervical neoplasia compared with those with normal control participants, but there was no statistical difference among types of cervical neoplasia. Serum anti-HPV 16 antibodies were also able to differentiate cervical neoplasia from a normal control participant and furthermore distinguished CIN 1 from CIN 2 and 3 (odd ratio 2.87 [1.43–5.78], P=.002). In cervical cancer, HPV 16 seropositivity was associated with prolonged disease-free survival according to the univariable analysis (hazard ratio=0.12 [0.01–0.94], P=.044). CONCLUSION: Serum anti-HPV 16 antibodies can distinguish cervical neoplasia from a normal control and has the advantage of identifying high-grade CIN. Moreover, in cervical cancer, HPV 16 seropositivity may be associated with a more favorable prognosis. LEVEL OF EVIDENCE: II

Peritoneal dissemination of follicular carcinoma arising from struma ovarii in a pregnant woman

1006 PERITONEAL DISSEMINATION OF FOLLICULAR CARCINOMA ARISING FROM STRUMA OVARII IN A PREGNANT WOMAN Bo Ram Choi, MD, Bo Wook Kim, MD, Sun Ok Yoon, MD, Young Tae Kim, MD, Sarah Lee, MD, Jae Hoon Kim, MD Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine; Department of Obstetrics and Gynecology, Korea Cancer Center Hospital; Department Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine; Departments of Obstetrics and Gynecology and Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

Mitochondrial reprogramming via ATP5H loss promotes multimodal cancer therapy resistance

The host immune system plays a pivotal role in the emergence of tumor cells that are refractory to multiple clinical interventions including immunotherapy, chemotherapy, and radiotherapy. Here, we examined the molecular mechanisms by which the immune system triggers cross-resistance to these interventions. By examining the biological changes in murine and tumor cells subjected to sequential rounds of in vitro or in vivo immune selection via cognate cytotoxic T lymphocytes, we found that multimodality resistance arises through a core metabolic reprogramming pathway instigated by epigenetic loss of the ATP synthase subunit ATP5H, which leads to ROS accumulation and HIF-1&agr; stabilization under normoxia. Furthermore, this pathway confers to tumor cells a stem-like and invasive phenotype. In vivo delivery of antioxidants reverses these phenotypic changes and resensitizes tumor cells to therapy. ATP5H loss in the tumor is strongly linked to failure of therapy, disease progression, and poor survival in patients with cancer. Collectively, our results reveal a mechanism underlying immune-driven multimodality resistance to cancer therapy and demonstrate that rational targeting of mitochondrial metabolic reprogramming in tumor cells may overcome this resistance. We believe these results hold important implications for the clinical management of cancer.