Loss of ALDH1A1 Expression Is an Early Event in the Pathogenesis of Ovarian High-grade Serous Carcinoma

M Herman Chui; Yihong Wang; Ren-Chin Wu; Jeffrey Seidman; Robert J Kurman; Tian-Li Wang; Ie-Ming Shih


Mod Pathol. 2015;28(3):437-445. 

In This Article

Abstract and Introduction


Tumor-initiating cells are thought to share features with normal somatic stem cells. In mice, stem cells at the ovarian hilum have been shown to express the stem cell marker, aldehyde dehydrogenase isoform 1A1 (ALDH1A1), and are prone to malignant transformation. The potential relevance of this finding to humans has not been established. In this study, we used immunohistochemistry to assess the distribution of ALDH1A1 staining in the epithelium of human fallopian tubes, with particular reference to the transition of tubal epithelium to mesothelium (ie, tubal–mesothelial junction), ovarian surface epithelium, as well as putative precursors of ovarian high-grade serous carcinoma, namely, serous tubal intraepithelial carcinoma and 'p53 signatures,' and overt serous carcinoma. Expression of ALDH1A1 was detected in both secretory and ciliated tubal epithelial cells, tubal–mesothelial junctions and ovarian surface epithelium, but was absent in serous tubal intraepithelial carcinoma and p53 signatures. Positive staining in high-grade serous carcinoma, when present, was typically limited to rare tumor cells. In silico analyses of the mRNA expression data set from The Cancer Genome Atlas revealed downregulation of ALDH1A1 transcripts in high-grade serous carcinoma relative to normal tubal epithelium, and no association between ALDH1A1 expression levels and overall survival. Our results do not support ALDH1A1 as a specific marker of stem cells in human fallopian tube and demonstrate that its loss of expression is an early event in the development of high-grade serous carcinoma.


Mounting evidence has shown that a significant proportion of pelvic high-grade serous carcinomas arise from a noninvasive occult carcinoma in the distal fallopian tube, designated 'serous tubal intraepithelial carcinoma'.[1] These lesions have been identified in a small percentage of prophylactic salpingo–oophorectomy specimens from women with germline BRCA mutations,[2,3] and in the tubal fimbriae from up to 60% of women with sporadic ovarian serous carcinomas.[4] Complete microscopic sectioning of fallopian tubes has also revealed focal proliferations of morphologically normal secretory cells that show diffuse TP53 immunoreactivity, termed 'p53 signatures,'[5] which may represent early clonal expansions of tumor-initiating cells.

Experimental work conducted in a variety of model systems across different tumor types have consistently demonstrated that tumor-initiating cells are derived from either a somatic stem cell or an early progenitor cell that has reacquired stem cell features.[6] This is in keeping with the concept that the capacity for indefinite proliferation, or self-renewal, is essential for malignant transformation.[7] Studies have also shown that only a fraction of cancer cells, termed 'cancer stem cells' are capable of forming tumors upon serial transplantation into immunocompromised mice, a technique used to assess self-renewal.[8]

One of the most commonly used markers for both normal and malignant stem cells is aldehyde dehydrogenase (ALDH) isoform 1A1 (ALDH1A1; previously known as ALDH1). ALDH1A1 is an enzyme involved in the metabolism of retinoic acid, which has been implicated in the regulation of cellular differentiation.[9,10] Multipotent stem cells in normal tissues have been shown to express ALDH1A1,[10,11] which has also been studied extensively as a candidate marker for cancer stem cells.[11–15] In mice, the 'ovarian hilum,' where nerves and blood vessels enter the ovary, is covered by a layer of cells that have been previously described as representing the transition between mesothelium lining the surface of the ovary and ovarian bursa, and ciliated columnar epithelium lining the mouse oviduct.[16] This region has been reported to be enriched for ALDH1A1-positive stem cells that show increased susceptibility to malignant transformation.[16]

In humans, the mesothelial lining of the ovarian surface epithelium extends over the ovarian hilum and is continuous with the mesovarium and broad ligament. The point of contact between mesothelium and Müllerian epithelium is positioned at multiple foci within the human fallopian tube fimbria and these 'tubal–mesothelial junctions' may be analogous to the junctional epithelium overlying the mouse ovarian hilum.[17] Whether stem cells reside in either the hilar area or the tubal–mesothelial junctions in humans, as observed in the mouse model, however, remains unknown.

To gain further insight into the phenotype of the cell of origin and the early events in the pathogenesis of high-grade serous carcinoma, we used immunohistochemistry to examine the pattern of ALDH1A1 expression in normal and lesional fallopian tube epithelium, including tubal–mesothelial junctions, endosalpingiosis, p53 signatures, serous tubal intraepithelial carcinoma, and high-grade serous carcinoma, as well as in ovarian surface epithelium, rete ovarii, and primary and recurrent ovarian serous carcinomas.