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. 2020 Dec 15:10:523989.
doi: 10.3389/fonc.2020.523989. eCollection 2020.

Proteomic Analysis of Pre-Invasive Serous Lesions of the Endometrium and Fallopian Tube Reveals Their Metastatic Potential

Mitchell Acland  1 , Georgia Arentz  1 , Max Mussared  2 , Fergus Whitehead  3 , Peter Hoffmann  4 , Manuela Klingler-Hoffmann  4 , Martin K Oehler  4   5   6
Affiliations

Proteomic Analysis of Pre-Invasive Serous Lesions of the Endometrium and Fallopian Tube Reveals Their Metastatic Potential

Mitchell Acland et al. Front Oncol. .

Abstract

Serous endometrial cancer (SEC) and high grade serous ovarian cancer (HGSOC) are aggressive gynecological malignancies with high rates of metastasis and poor prognosis. Endometrial intraepithelial carcinoma (EIC), the precursor for SEC, and serous tubal intraepithelial carcinoma (STIC), believed to be the precursor lesion for HGSOC, can also be associated with intraabdominal spread. To provide insight into the etiology of these precancerous lesions and to explore the potential molecular mechanisms underlying their metastatic behavior, we performed a proteomic mass spectrometry analysis in a patient with synchronous EIC and STIC. Through histological and molecular identification of precancerous lesions followed by laser capture microdissection, we were able to identify over 450 proteins within the precancerous lesions and adjacent healthy tissue. The proteomic analysis of STIC and EIC showed remarkable overlap in the proteomic patterns, reflecting early neoplastic changes in proliferation, loss of polarity and attachment. Our proteomic analysis showed that both EIC and STIC, despite being regarded as premalignant lesions, have metastatic potential, which correlates with the common presentation of invasive serous gynecological malignancies at advanced stage.

Keywords: endometrial intraepithelial carcinoma; high grade serous ovarian carcinoma; proteomics; serous endometrial carcinoma; serous tubal intraepithelial carcinoma.

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Conflict of interest statement

Author FW was employed by the company Clinpath. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Hematoxylin and Eosin stained fallopian tube (A, B) and endometrium tissue (C, D) at 6× (A, C) and 12× (B, D) magnification. Areas of STIC (B) and EIC (D) are indicated by the red arrows.
Figure 2
Figure 2
Venn diagram describing overlapping protein identifications in endometrial intraepithelial carcinoma (EIC), healthy endometrium (HE), serous tubal intraepithelial carcinoma (STIC) and healthy fallopian tube (HFT). A significant overlap of (348 proteins) is observed between EIC and STIC (diagram generated at http://bioinformatics.psb.ugent.be/webtools/Venn/).
Figure 3
Figure 3
Gene expression of (A) CAPS and (B) EPCAM in early stage I serous ovarian cancer tissues (SOC) (n = 8) compared to normal peritoneum (NP) (n = 10). Expression levels were extracted from the data of Yoshihara et al. (44) (GEO Accession GSE12470) via the R package CuratedOvarianData (http://www.ncbi.nlm.nih.gov/geo/).
Figure 4
Figure 4
Gene expression analysis of (A) CAPS and (B) EPCAM in early stage endometrioid (EEC) (n = 79) and serous (SEC) endometrial carcinoma (n = 12) compared to normal endometrium (NE) (n = 12). Expression levels were extracted from the data of Days et al. (46) (GEO Accession GDS4589, http://www.ncbi.nlm.nih.gov/geo/) using R.
Figure 5
Figure 5
Expression levels of genes whose protein abundance is specific to certain to gynaecological tissues. (A) SORD, (B) TPP3, and (C) VCAN in 4 normal ovarian (NO), 8 clear cell (CCOC), 37 endometrial (EEOC), 13 mucinous (MOC), and 41 serous (SOC) ovarian carcinomas. Blue dots represent data points from late stage patients while the red represent early stage. Data gathered from Hendrix et al. (45) (GEO Accession GSE6008, http://www.ncbi.nlm.nih.gov/geo/).
Figure 6
Figure 6
Expression levels of genes whose proteins are associated with specific gynecological tissues. (A) ERO1A, (B) TPPP3, (C) SPATA18, (D) SORD, and (E) VCAN in 13 copy number (CN) high, 16 micro satellite instability (MSI) hypermutated, 4 POLE ultra-mutated, and 15 CN low. Here, the blue dots represent data points from late stage patients while the red represent early stage cancers. Data from Kandolth et al. (4) (https://gdc.cancer.gov/node/875).
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