MUC1 Positive, Kras and Pten Driven Mouse Gynecologic Tumors Replicate Human Tumors and Vary in Survival and Nuclear Grade Based on Anatomical Location

Abstract

Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP) mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre) in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus). Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015), yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.

Emerging and Evolving Ovarian Cancer Animal Models

“…To compare tumorigenesis in the ovary, oviduct, and endometrium using the same genetic backgrounds, a triple transgenic mouse model was created. 47 In these mice, Kras G12D (using a LSL cassette) is induced, and floxed Pten is deleted using Adeno-Cre in different locations of the female reproductive tract. 48 Additionally, these transgenic mice also express the human glycoprotein MUC1 that is often overexpressed in OC.…”

“… 48 Injection of Adeno-Cre into the ovary, oviduct, or uterus resulted in the formation of epithelial tumors capable of metastasis, spreading to the pancreas and diaphragm. 47 However, the nuclear grade of the tumors and survival of the mice varied depending on the anatomical site of injection. 47 Tumors arising from ovaries, the oviduct, and uterus generated endometrioid histology and metastasis to spleen, diaphragm, and liver were detected.…”

“… 47 However, the nuclear grade of the tumors and survival of the mice varied depending on the anatomical site of injection. 47 Tumors arising from ovaries, the oviduct, and uterus generated endometrioid histology and metastasis to spleen, diaphragm, and liver were detected. 47 The oviduct tumors developed into poorly differentiated high-grade tumors, while ovarian and uterine tumors were more differentiated.…”

“… 47 Tumors arising from ovaries, the oviduct, and uterus generated endometrioid histology and metastasis to spleen, diaphragm, and liver were detected. 47 The oviduct tumors developed into poorly differentiated high-grade tumors, while ovarian and uterine tumors were more differentiated. 47 Mice with ovarian and oviduct tumors exhibited the shortest mean survival times compared to mice with uterine tumors (89, 82, and 132.5 days, respectively).…”

“… 47 The oviduct tumors developed into poorly differentiated high-grade tumors, while ovarian and uterine tumors were more differentiated. 47 Mice with ovarian and oviduct tumors exhibited the shortest mean survival times compared to mice with uterine tumors (89, 82, and 132.5 days, respectively). A key feature of this model is that overexpression of MUC1 results in a similar immune response as that seen in human patients.…”