SALL4 Expression in Germ Cell and Non–Germ Cell Tumors

Abstract

SALL4 transcription factor is associated with embryonic cell pluripotency and has been shown as a useful immunohistochemical marker for germ cell tumors. However, information of SALL4 distribution in normal human tissues and non germ-cell tumors is limited. In this study we examined normal human tissues and 3215 tumors for SALL4 expression using a monoclonal antibody 6E3 and automated immunohistochemistry. In a 10th week embryo, SALL4 was expressed in ovocytes, intestine, kidney, and some hepatocytes. In adult tissues, it was only detected in germ cells. SALL4 was consistently expressed in all germ cell tumors except some trophoblastic tumors and mature components of teratomas, where it was selectively expressed in intestinal-like and some squamous epithelia. In non germ-cell carcinomas, SALL4 was detected in 20% of cases or more of serous carcinoma of ovary, urothelial high-grade carcinoma, and gastric adenocarcinoma (especially the intestinal type). SALL4 was only rarely (≤5%) expressed in mammary, colorectal, prostatic, and squamous cell carcinomas. Many SALL4 positive carcinomas showed poorly differentiated patterns and some showed positivity in most tumor cells mimicking the expression in germ cell tumors. SALL4 was commonly expressed in rhabdoid tumors of kidney and extrarenal sites, and in Wilms tumor. Expression of SALL4 was rare in other mesenchymal and neuroendocrine tumors but was occasionally detected in melanoma, desmoplastic small round cell tumor, epithelioid sarcoma, and rhabdomyosarcoma. All hematopoietic tumors were negative. SALL4 is an excellent marker of non-teratomatous germ cell tumors, but it is also expressed in other tumors, sometimes extensively. Such expression may reflect stem-cell like differentiation and must be considered when using SALL4 as a marker for germ cell tumors. Observed lack of other pluripotency factors, OCT4 and NANOG, in SALL4-positive non-germ cell tumors can also be diagnostically helpful.

SALL4, the missing link between stem cells, development and cancer

“…Analyses of its expression and epigenetic status have shown that SALL4 is de-regulated and aberrantly expressed in various cancers (Review in 64 ) such as leukemia 65 , germ cell tumors 6667 , hepatocellular carcinoma (HCC) 2468 , gastric cancer 20,69–73 , colorectal carcinoma 74–76 , esophageal squamous cell carcinoma 77,78 , breast cancer 79–81 , endometrial cancer 82,83 , lung cancer 84–86 and glioma 87 . Functionally, SALL4 is important for the survival 38,80,82,88–93 , drug resistance 82,94 and metastasis 69,82 of many of these cancer cells (Figure 4).…”

“…In yolk sac tumors and primary extragonadal germ cell tumors, one study reported that the circulating tumor cells are detectable by anti-SALL4 antibody in peripheral blood samples, making this protein a more sensitive marker than α-fetoprotein and glypican-3 107 . In addition, SALL4 is expressed in a majority of malignant rhabdoid tumors (MRTs) 20108109110111 but rarely expressed in epithelioid sarcomas. Therefore, SALL4 immunoexpression may be a useful diagnostic tool to distinguish epitheloid sarcoma from malignant rhabdoid tumor.…”

“…Finally, by E11.5, Sall4 expression is observed in the midbrain, the rostral edge of the forebrain, maxillary arch, genital tubercle, limb buds, tail, and left ventricular myocardium 17,18 . In adult mice, Sall4 expression is mostly restricted to germ cells, wherein it is highly expressed in undifferentiated spermatogonia and oocytes in primordial, primary, and secondary follicles 192021 . Similarly, expression of SALL4 in adult human tissue is restricted to the testis and ovary 4 (Figure 2).…”

The nucleosome remodeling and deacetylase complex in development and disease

“…Similar effects were noted with HDAC inhibitors, suggesting that the tumor suppressing effect of abrogating the SALL-NuRD interaction is dependent on reduction of NuRD complex associated HDAC activity. SALL4 overexpression has been noted in other tumors [90] and thus this strategy may have broader application as a new therapeutic target for specific cancers. An excellent candidate is uterine cancer.…”

“…Thus, it is plausible that disruption of SALL4-NuRD interaction in this tumor may also be beneficial. SALL family proteins are overexpressed or mutated in various cancers and its interaction with NuRD may emerge as an important mechanism for tumorogenesis or metastasis [90, 92, 93]. …”