KRAS mutation coupled with p53 loss is sufficient to induce ovarian carcinosarcomas in mice

• Published in: International journal of cancer Vol. 140; no. 8; pp. 1860 - 1869
• Main Authors: Tang, Feng‐Hsiang, Hsieh, Tsung‐Hua, Hsu, Chia‐Yi, Lin, Hsiao‐Yun, Long, Cheng‐Yu, Cheng, Kuang‐Hung, Tsai, Eing‐Mei
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.04.2017
• Subjects: Animals; Cancer; Carcinosarcoma - genetics; Carcinosarcoma - pathology; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Clonal deletion; Disease Models, Animal; Endometriosis; Epithelium; Female; Gene deletion; Genetic transformation; Humans; K-Ras protein; Kidneys; K‐rasG12D; Malignancy; Medical research; Metastases; Mice; Mice, Transgenic; Mutation; Organs; Ovarian cancer; Ovarian carcinoma; ovarian carcinosarcoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Ovaries; p53 Protein; p53loxP/loxP; Pathogenesis; Proto-Oncogene Proteins p21(ras) - genetics; Rodents; Spleen; Transgenic mice; Tumor cell lines; Tumor Suppressor Protein p53 - genetics; K-rasG12D; p53loxP/loxP; ovarian carcinosarcoma
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30591

Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K‐rasG12Dp53loxP/loxP and found that K‐ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated. Induction was widely metastatic and spread to abdominal organs including liver, spleen, and kidney at 4 wk. We also confirmed the role of K‐rasG12D in ovarian cancer cell lines MCAS and PA‐1 and showed that K‐rasG12D overexpression strongly induced cell proliferation, migration, and invasion. The ovarian cancer model we developed recapitulates the specific tumor histomorphology and the probable mechanism of malignant transformation in endometriosis. What's new? Significant progress in the establishment of epithelial ovarian cancer mouse models has been achieved recently, but most concern well‐differentiated or undifferentiated cancer. To understand the genetic link between endometriosis and ovarian cancer, here the authors established transgenic mice that carry both the conditional oncogenic K‐rasG12D mutation and p53 deletion to induce precursor lesions and characterized the poorly differentiated histopathology of preneoplastic epithelium. The LSL‐K‐rasG12D/+p53loxp/loxp ovarian cancer model recapitulates the specific tumor histomorphology and the probable mechanism of malignant transformation in endometriosis and may be used to study the signaling pathways and mechanisms regulated by K‐ras and p53 in ovarian cancer.