Dataset Information

Changes in the tumor microenvironment mark transition from serous borderline tumor to low grade serous carcinoma

ABSTRACT: Low grade serous ovarian cancer (LGSC) is a rare subtype of ovarian cancer, characterized by a slow growth rate, resistance to current treatment regimens, multiple recurrences and poor survival. LGSC arise from serous borderline tumor (SBT), however the mechanism of transformation is poorly understood. To better understand the biology of serous ovarian tumors, we performed whole proteome profiling of LGSC, SBT and the more common high grade serous (HGSC) ovarian tumors. Proteins associated with the tumor microenvironment were differentially expressed between LGSC and SBT or HGSC. In particular, fibroblast activation protein (FAP), a protein expressed in cancer associated fibroblasts, is abundantly expressed in LGSC. Furthermore, Tregs and M2 macrophages are more abundant in the stroma of LGSC compared to SBT. Together these data suggest that the tumor microenvironment provides a supportive environment for LGSC tumorigenesis and progression, and that targeting the tumor microenvironment of LGSC may be a viable therapeutic strategy.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Ovary Cancer Cell

SUBMITTER: Gian Luca Negri

LAB HEAD: Gregg Morin

PROVIDER: PXD046360 | Pride | 2024-08-15

REPOSITORIES: Pride

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			Action	DRS
	20220517_BMBP_SS_Huntsman_SBOT_noID_B1F1.raw	Raw
	20220517_BMBP_SS_Huntsman_SBOT_noID_B1F10.raw	Raw
	20220517_BMBP_SS_Huntsman_SBOT_noID_B1F11.raw	Raw
	20220517_BMBP_SS_Huntsman_SBOT_noID_B1F12.raw	Raw
	20220517_BMBP_SS_Huntsman_SBOT_noID_B1F2.raw	Raw

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Changes in the tumour microenvironment mark the transition from serous borderline tumour to low-grade serous carcinoma.

Vallejos Rodrigo R Zhantuyakova Almira A Negri Gian Luca GL Martin Spencer D SD Spencer Sandra E SE Thornton Shelby S Leung Samuel S Lynch Branden B Qin Yimei Y Chow Christine C Liang Brooke B Zdravko Sabrina S Douglas J Maxwell JM Milne Katy K Mateyko Bridget B Nelson Brad H BH Howitt Brooke E BE Kommoss Felix Kf FK Horn Lars-Christian LC Hoang Lien L Singh Naveena N Morin Gregg B GB Huntsman David G DG Cochrane Dawn D

The Journal of pathology 20240731 2

Low-grade serous ovarian carcinoma (LGSC) is a rare and lethal subtype of ovarian cancer. LGSC is pathologically, biologically, and clinically distinct from the more common high-grade serous ovarian carcinoma (HGSC). LGSC arises from serous borderline ovarian tumours (SBTs). The mechanism of transformation for SBTs to LGSC remains poorly understood. To better understand the biology of LGSC, we performed whole proteome profiling of formalin-fixed, paraffin-embedded tissue blocks of LGSC (n = 11), ...[more]

PMID: 39081243

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Project description:Recent evidence suggests that ovarian high-grade serous carcinoma (HGSC) originates from the epithelium of the fallopian tube. However, most mouse models are based on the previous prevailing view that ovarian cancer develops from the transformation of the ovarian surface epithelium. Here, we report the extensive histological and molecular characterization of the mogp-TAg transgenic mouse, which expresses the SV40 large T-antigen (TAg) under the control of the mouse müllerian-specific Ovgp-1 promoter. Histologic analysis of the fallopian tubes of mogp-TAg mice identified a variety of neoplastic lesions analogous to those described as precursors to ovarian HGSC. We identified areas of normal appearing p53-positive epithelium that are similar to “p53 signatures” in the human fallopian tube. More advanced proliferative lesions with nuclear atypia and epithelial stratification were also identified that were morphologically and immunohistochemically reminiscent of human serous tubal intraepithelial carcinoma (STIC), a potential precursor of ovarian HGSC. Beside these noninvasive precursor lesions, we also identified invasive adenocarcinoma in the ovary of 56% of the mice. Microarray analysis revealed several genes differentially expressed between the fallopian tube of mogp-TAg and WT C57BL/6. One of these genes, Top2a, which encodes topoisomerase II-alpha, was shown by immunohistochemistry to be concurrently expressed with elevated p53 and specifically elevated in mouse STICs, but not in surrounding tissues. TOP2A protein was also found elevated in human STICs, low-grade, and high-grade serous carcinoma. The mouse model reported here displays a progression from normal tubal epithelium to invasive HGSC in the ovary, and therefore closely simulates the current emerging model of human ovarian HGSC pathogenesis. This mouse therefore has the potential to be a very useful new model for elucidating the mechanisms of serous ovarian tumorigenesis, as well as for developing novel approaches for the prevention, diagnosis, and therapy of this disease. Keywords: transgenic mouse model, ovarian cancer, fallopian tube, intraepithelial carcinoma 6 mouse fallopian tubes (FT) were analyzed with experimental repeats; 3 wildtype C57BL6 mice (FT) and 3 transgenic mogp-TAg (FT), with one set of each at 7, 8 and 9 weeks of age.