Cancer/testis (CT) antigens, carcinogenesis and spermatogenesis

Abstract

During spermatogenesis, spermatogonial stem cells, undifferentiated and differentiated spermatogonia, spermatocytes, spermatids and spermatozoa all express specific antigens, yet the functions of many of these antigens remain unexplored. Studies in the past three decades have shown that many of these transiently expressed genes in developing germ cells are proto-oncogenes and oncogenes, which are expressed only in the testis and various types of cancers in humans and rodents. As such, these antigens are designated cancer/testis antigens (CT antigens). Since the early 1980s, about 70 families of CT antigens have been identified with over 140 members are known to date. Due to their restricted expression in the testis and in various tumors in humans, they have been used as the target of immunotherapy. Multiple clinical trials at different phases are now being conducted with some promising results. Interestingly, in a significant number of cancer patients, antibodies against some of these CT antigens were detected in their sera. However, antibodies against these CT antigens in humans under normal physiological conditions have yet to be reported even though many of these antigens are residing outside of the blood-testis barrier (BTB), such as in the basal compartment of the seminiferous epithelium and in the stem cell niche in the testis. In this review, we summarize latest findings in the field regarding several selected CT antigens which may be intimately related to spermatogenesis due to their unusual restricted expression during different discrete events of spermatogenesis, such as cell cycle progression, meiosis and spermiogenesis. This information should be helpful to investigators in the field to study the roles of these oncogenes in spermatogenesis.

Keywords: cancer; cancer/testis antigens; cell cycle progression; meiosis; mitosis; seminiferous epithelial cycle; spermatids; spermatocytes; spermatogenesis; spermatogonia; spermatogonial stem cells; spermatozoa; testis; tumorigenesis.

Figures

Figure 1

Morphological and cellular features of spermatogenesis in the mammalian testis. The anatomical features of the rat testis shown here (A) share many of the feature similar to other mammalian testes including humans, and the schematic drawing shown in (B) depicts the major cellular events of spermatogenesis, namely spermatogonia/SSC self-renewal via mitosis and differentiation to type B spermatogonia, which in turn transform to preleptotene spermatocytes. Preleptotene spermatocytes are the germ cells residing in the basal compartment traverse the blood-testis barrier (BTB) at stage VIII of the epithelial cycle that enter the adluminal (apical) compartment while differentiate into leptotene, zygote and then pachytene spermatocytes in a process known as cell cycle progression. Diplotene spermatocytes eventually enter meiosis I to be immediately followed by meiosis II at stage XIV as shown in (A) to form haploid round spermatids (step I spermatids). Spermatids undergo spermiogenesis to form elongating and elongated spermatids involving 19 and 16 steps in rats and mice, respectively. Elongated spermatids transform into spermatozoa following the shredding of the residual body to be phagocytosed by the Sertoli cells to allow the release of sperm at spermiation. The fine morphological features of some of these germ cells are also depicted in (B). It is noted that the seminiferous epithelium is resting on the tunica propria, which is composed of an acellular zone namely basement membrane (a modified form of extracellular matrix) and type I collagen layer, and a cellular zone of peritubular myoid cell layer and the lymphatic microvessel. It is noted that the seminiferous epithelium is composed of only Sertoli and germ cells without the presence of any blood vessels and nerve fibers since all microvessels are restricted to the interstitial space between seminiferous tubules. The BTB also physically divides the seminiferous epithelium into the basal and adluminal (apical) compartments. Different cancer/testis (CT) antigens are expressed throughout spermatogenesis with unique patterns of cellular expression among different types of germ cells. PLS, preleptotene spermatocyte; RS, round spermatid.

Figure 2

A schematic drawing illustrating the restricted expression of different CT antigens in germ cells during spermatogenesis. The part on the right depicts different germ cell types during spermatogenesis, and the left part illustrates the unique expression patterns of seven different CT antigens in different germ cell types, illustrating their possible involvement in different phases of spermatogenesis. These CT antigens, besides their restricted expression in the testis but not other normal human cells/tissues, they are highly expressed in cancer cells. As such, many of these antigens are the targets of immunotherapy and vaccine development for cancer treatment. Yet their functional significance in the testis remains largely unexplored.