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Cancer/testis antigens, gametogenesis and cancer

Key Points

  • Cancer/testis (CT) antigens are normally expressed by gametes and trophoblasts, and are aberrantly expressed in a range of human cancers.

  • So far, 44 distinct CT-antigen families, some of which have multiple members, have been identified.

  • CT antigens are immunogenic and, as a result, have the potential to be used as tumour vaccines.

  • CT antigens can be divided between those that are encoded on the X chromosome (CT-X antigens) and those that are not (non-X CT antigens).

  • CT-X antigens tend to form recently expanded gene families that are usually highly expressed in the spermatogonia — mitotically proliferating germ cells. The CT-X genes are frequently co-expressed in cancer cells, which tend to express several CT antigens.

  • The genes for the Non-X CT antigens are distributed throughout the genome. In the testis, they are usually expressed in the spermatocytes and many have roles in meiosis. Their aberrant expression in cancer cells might cause abnormal chromosome segregation and aneuploidy.

  • Methylated CpG islands associated with the CT-X genes in normal somatic cells become demethylated in cancer cells, indicating activation of their expression. Although global hypomethylation is frequently put forward as the basis of CT-antigen expression in cancer cells, it will be important to define the events leading to the hypomethylated state.

  • MAGEA1 has been shown to be a transcriptional co-repressor that interacts with SKI interacting protein and autonomously represses transcription. Other CT-X antigens also control gene expression and directly influence the sensitivity of cancer cell lines to cytotoxic assault as well as cell proliferation.

  • As germline stem cells and their trophoblastic derivatives share many characteristics with tumour cells, the activation of normally silent germline-specific genes in cancer stem cells (gametic recapitulation) could mediate the malignant phenotype in the absence of mutations in known oncogenes and tumour-suppressor genes.

Abstract

Cancer/testis (CT) antigens, of which more than 40 have now been identified, are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumour types, including melanoma, and carcinomas of the bladder, lung and liver. These immunogenic proteins are being vigorously pursued as targets for therapeutic cancer vaccines. CT antigens are also being evaluated for their role in oncogenesis — recapitulation of portions of the germline gene-expression programme might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, hypomethylation and metastatic capacity.

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Figure 1: Shared characteristics of germ cells and cancer cells.
Figure 2: Cancer/testis antigen expression in normal and tumour tissues.

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Acknowledgements

We thank C. Pentlow for her diligent literature searches and preparation of background material used in the preparation of this review.

Author information

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Correspondence to Andrew J. G. Simpson.

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Related links

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DATABASES

Entrez Gene

ADAM2

BAGE

BRDT

GAGE1

MAGEA1

MAGEA11

MAGEA2

MAGEA3

MAGEA4

MAGEA6

MAGED1

NXF2

NY-ESO-1

PAX9

PLU-1

SCP1

SKIP

SLCO6A1

SPO11

TAF7L

TPX1

National Cancer Institute

bladder cancer

lung cancer

melanoma

ovarian cancer

FURTHER INFORMATION

Cancer/Testis Gene Database

Ludwig Institute for Cancer Research

Glossary

TROPHOBLASTS

The outermost layer of cells of the blastocyst that attaches the fertilized ovum to the uterine wall and serves as a nutritive pathway for the embryo. Trophoblasts invade and penetrate, permiting the blastocyst to burrow into the central layer of endometrium. Early blastocyst trophoblasts differentiate into all the other cell types found in the human placenta.

CHORIONIC GONADOTROPIN

A hormone produced by the placenta that maintains the corpus luteum during pregnancy.

AUTOLOGOUS TYPING

An approach developed to test whether patients with cancer develop specific antibodies or T cells to tumour-restricted antigens. Analysis was restricted to assays including normal (fibroblasts) and malignant cells from the same (autologous) patient. The specificity was further confirmed by absorption analysis with autologous normal cells.

SPERMATOGONIA

The germ cells of spermatogenesis. Unlike mammalian oogonia, they continue to divide throughout life and give rise to spermatocytes

SPERMATOCYTES

Diploid cells that undergo meiosis to form four spermatids. A primary spermatocyte divides into two secondary spermatocytes, which in turn divide to form the spermatids.

PACLITAXEL

A naturally occurring compound, originally purified from the pacific yew tree, that stabilizes microtubules and has antitumour activity.

DOXORUBICIN

A chemotherapeutic drug that induces breaks in DNA strands, which initiates apoptosis.

PACHYTENE

The third stage of the prophase of meiosis. In this phase the homologous chromosomes become short and thick and divide into four distinct chromatids.

PRIMORDIAL GERM CELLS

The progenitor cells of gametogenesis.

SYNAPTONEMAL COMPLEX

A protein structure that forms between two homologous chromosomes during meiosis and that mediates chromosome pairing, synapsis and recombination. The synaptonemal complex is a tripartite structure, consisting of two parallel lateral regions and a central element.

TRANSVERSE FILAMENTS

Proteins that connect the two lateral elements of the synaptonemal complex.

ANEUPLOIDY

The state of having an abnormal number of chromosomes. Most human epithelial cancers harbour genomes that are characterized by gross aneuploidy.

KARYOTYPE

A complete description of the chromosomes present in a cell; characterized by numerical and structural abnormalities in most cancers.

DIPLOTENE

The stage of the first meiotic prophase, following the pachytene, in which the two chromosomes in each bivalent begin to repel one another and a split occurs between the chromosomes, which are then held together by regions where exchanges have taken place (chiasmata) during crossing over.

SPERMATID

Any of the four haploid cells formed by meiosis in a male organism that develop into spermatozoa without further division.

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Simpson, A., Caballero, O., Jungbluth, A. et al. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5, 615–625 (2005). https://doi.org/10.1038/nrc1669

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