Weiwei Shan

Inflammation: a hidden path to breaking the spell of ovarian cancer.

Epithelial ovarian cancer is a highly lethal gynecological cancer for which overall prognosis has remained poor over the past few decades. A number of theories have been postulated in an effort to explain the etiology of epithelial ovarian cancer, each of which has been both applauded and doubted. Of note, these theories likely are not mutually exclusive, as they all converge more or less on the role of inflammation in promoting ovarian tumorigenesis. In this review, we describe the latest studies on the role of inflammation in the initiation and progression of EOC from three major aspects: physiological functions of a normal ovary, potential involvement of the fallopian tube in the initiation of EOC, and the strong impact of the cellular microenvironment on the development of the disease.

Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through defined genetic modifications.

Recent studies have suggested that some ovarian and pelvic serous carcinomas could originate from the fimbriated end of the distal fallopian tube. To test this hypothesis, we immortalized a normal human fallopian tube epithelial (FTE) cell line by using retrovirus-mediated overexpression of the early region of the SV40 T/t antigens and the human telomerase reverse transcriptase subunit (hTERT). These immortalized FTEs were then transformed by ectopic expression of oncogenic human HRASV12. Tumorigenicity of the immortalized and/or transformed cells was subsequently tested by anchorage-independence growth assay and inoculation into nude mice via subcutaneous and intraperitoneal injection. As expected, the HRASV12-transformed FTEs produced tumors through both subcutaneous and intraperitoneal injections, whereas no tumor growth was observed in immortalized FTEs. Unexpectedly, histopathological examination of tumors resulting from subcutaneous as well as intraperitoneal injections revealed largely poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma. The tumor implants invaded extensively to the liver, colon, spleen, omentum, adrenal gland and renal capsule. Immunohistochemical staining of tumor cells showed positive staining for the epithelial cell markers cytokeratin AE1/AE3 and Müllerian lineage marker PAX8. Our study demonstrates that FTEs can generate poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma through genetic modifications. Thus, we provide the first experimental evidence that fimbrial epithelial cells of the fallopian tube could be a potential source of ovarian mucinous adenocarcinoma.

Epithelial ovarian cancer: focus on genetics and animal models.

Despite rapid advances in understanding ovarian cancer etiology, epithelial ovarian cancer remains the most lethal form of gynecologic cancers in the United States. The four morphologically-defined epithelial ovarian cancer subtypes–serous, endometrioid, mucinous, and clear cell carcinomas–are generally believed to originate from ovarian epithelial cells. Although it remains unclear how this single cell layer gives rise to morphologically distinct cancers, it has been suggested that early genetic events may direct the differentiation of ovarian epithelial cells. A number of genetic alterations are frequently encountered during ovarian tumorigenesis, including oncogenic activities of KRAS, BRAF, and AKT, and silencing mutations of TP53, RB, and PTEN. However, knowledge about how these genetic elements are coordinated during ovarian cancer initiation and progression is very limited. The establishment of cell-culture systems and rodent-based models has made big strides towards a better understanding of the genetic bases of human epithelial ovarian tumorigenesis. More importantly, the rise of genetically-engineered rodent and human models, particularly in the past five years, has provided key insight in the role of specific genes during ovarian tumorigenesis. In this review, we offer a comprehensive coverage of currently-available in vitro and in vivo models of human epithelial ovarian cancer, focusing on latest updates of genetically-modified rodent and human models and the valuable information conveyed by them.

Morphological and molecular basis of ovarian serous carcinoma

Serous carcinoma is the most common type of epithelial ovarian cancer. In this review, we provide a comprehensive picture of ovarian serous cancers from multiple aspects: the first part of this review summarizes the morphological, histological, and immunological signatures of ovarian serous carcinoma; subsequently, we review the history of the evolvement of different grading systems used in ovarian serous cancer; in the end, we focus on characterizing the genetics that underlie the 2-tiered pathways through which ovarian serous cancers are believed to arise: the low-grade and the high-grade pathways.

Prospective prediction of resistance to neoadjuvant therapy in patients with locoregional esophageal adenocarcinoma

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Gastrointestinal Cancer: Targets and Therapy 2015:5 53–59 Gastrointestinal Cancer: Targets and Therapy Dovepress

Intended use for a neoadjuvant chemoradiation response prediction test for locally advanced esophageal adenocarcinoma: a survey analysis of thoracic surgeons in the US.

Abstract Objective: A multi-analyte immunohistochemistry (IHC) based test (DecisionDx-EC *DecisionDx-EC, Castle Biosciences, Incorporated, Friendswood, TX. Hereafter referred to as the “IHC-based test”.) was developed and proved able to accurately predict response to neoadjuvant chemoradiotherapy (neoCTRT) in esophageal adenocarcinoma (EC) patients with locoregional disease. A survey was conducted with surgeons attending the 2013 Society of Thoracic Surgeons Annual Conference to assess their intention to change standard of care patient treatment based on predictive results obtained from this test. Research design and methods: Fifty-seven thoracic surgeons were provided a questionnaire regarding the current clinical management of locoregional EC patients, and their intention to change management strategy if a patient is predicted by the multi-analyte IHC-based test to experience pathological complete response (pathCR) or extremely resistant to neoCTRT (exCTRT). Results: Forty-four out of 46 enrolled respondents indicated that they administer neoCTRT followed by surgery to treat locally advanced EC. Fifteen (32%) respondents presently prescribing neoCTRT to EC patients acknowledged that a pathCR prediction provided by the multi-analyte IHC-based test would change their current regimens. Conversely, 28 surgeons (61%) would be willing to adjust their current strategy for patients predicted to be resistant to neoCTRT, significantly more than the case where patients are predicted to be pathCR (p = 0.01). Twenty-five percent (25%) of surgeons willing to adjust treatment in response to a patient being a potential exCTRT chose to remove CTRT from the strategy, and instead would choose surgery alone for these patients. Conclusions: Results from the current survey show that patients’ response to neoCTRT predicted by the multi-analyte IHC-based test has a significant influence on the decision-making process in the clinic. Nearly twice as many surgeons stated an intention to change strategy with the knowledge that the patient is likely to have extreme resistance to planned treatments than when one is a potential responder. The current survey study is limited by its ‘intended use’ nature, therefore does not reflect physicians’ real action in the clinic upon implementation of this test. However, survey results strongly suggest that use of the IHC-based predictive test is of great interest to physicians, and would likely contribute to more individualized treatment for patients with distinct sensitivity to neoCTRT.

Abstract 4230: The pro-inflammatory secretory phenotype and selection of stem-like cells in RAS-transformed ovarian epithelial cells

Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer in the United States. Previously, our laboratory has successfully transformed human ovarian epithelial cells with oncogenic RAS carrying an activating mutation at valine 12 (HRAS V12 ) (T29H cells). By cDNA expression microarray we found that T29H cells exhibited marked activation of a wide spectrum of inflammatory genes and generated a pro-inflammatory phenotype. In this report, we identified a much more malignant phenotype in ovarian tumor explants derived from T29H (hereby denoted T29HT) cells, manifested by a significantly shorter latency of tumor onset after inoculation of T29HT cells back into nude mice than that of the parental T29H cells, suggesting that the T29H cells underwent a selective process in vivo that was favorable to the enhancement of tumorigenicity. By examining the ability of cells to form spheroids in suspension culture and staining spheroids with stem cell marker CD44, we showed that T29HT cells may contain a larger population of potential stem-like cells than do T29H cells. Western blot analysis confirmed higher expression levels of CD44 and genes involved in epithelial mesenchymal transition (EMT) in T29HT cells than in T29H cells. Our results suggest that T29H cells may acquire augmented malignancy in vivo by expanding the pool of potential cancer stem-like cells, and HRAS V12 -induced pro-inflammatory factors may play pivotal roles in mediating this effect. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4230.