The human male germ line is passed on via the production of haploid sperm, which,
upon fusion with the female gamete, the ovum, will form a diploid zygote that will
ultimately become a genetically unique individual. Male gametogenesis occurs throughout
the lifespan of adult males. Sperm production is restricted to the seminiferous tubules
of the testis, and this process is continually fed by the mitotic proliferation of
germline stem cells (GSCs). The GSCs are a sub-group of spermatagonial cells, which
are found at the basal layer of the seminiferous tubules. Upon receipt of differentiation
signals, spermatagonial cells will undergo differentiation, first maturing to primary
spermatocytes and then ultimately through to fully differentiated spermatozoa. During
this cellular differentiation, meiosis occurs, reducing the chromosomal content from
diploid to haploid status and driving genetic variation.
Spermatagonial stem cell maintenance, spermatogenic cellular differentiation, and
the reductional chromosome segregation of meiosis requires an array of molecular orchestrators
that are unique to the germline, and there are a large number of genes that are specifically
activated to regulate distinct processes within the spermatogenic program. These genes
are regulated in a highly restricted tissue-specific fashion, and many are tightly
silenced in somatic tissues. Male germline genes have been reported to be activated
in cancers and can encode antigens known as the cancer/testis antigens (CTAs).
1
CTAs have garnered much interest, as their tight cancer-restricted profile makes them
important potential targets for cancer immunotherapies and as diagnostic and prognostic
markers;
1
indeed, recent seminal work has also demonstrated that specific assessment of germline
gene expression profiles in tumors can be used for highly accurate prognostic stratification
in cancer patients.
2
Most of the originally identified CTA genes (also referred to as CT genes if an associated
antigen has not yet been demonstrated) are encoded by large paralogous gene families
located on the X chromosome. The X chromosome becomes inactivated on entry into meiosis,
however, leading Feichtinger and coworkers
3
,
4
to speculate that there may be a substantial number of additional genes encoding meiosis-specific
proteins that could potentially serve as clinically and functionally important factors.
Through the meta-analysis of clinical cancer gene expression data sets performed by
this group, the CT gene family has now been extended to encompass many more single-copy,
autosomally encoded genes.
3
,
4
Aside from the unquestionably important potential for clinical application as biomarkers
and immunotherapeutic targets, CTA/meiosis-associated genes and their products pose
a bigger question that could ultimately reveal a previously unidentified weakness
of cancer cells that may provide new therapeutic opportunities. There is increasing
evidence supporting the view that CT genes are not simply passively activated as a
byproduct of the oncogenic process, and there is a growing consensus that CT genes
can actually drive oncogenesis and tumor drug resistance. This is illustrated by 2
additional seminal studies. First Janic and coworkers
5
demonstrated that germline genes were activated in l(3)mbt tumors in Drosophila melanogaster,
and that some of these were required to promote tumor formation; subsequent meta-analysis
of human cancer gene expression data sets by Feichtinger and colleagues
6
indicated that the human orthologs of the these germline genes were also extensively
activated in a wide range of human tumors, inferring that an oncogenic soma-to-germline
transition could be a feature of many human cancers. Second, in a distinct seminal
study by Whitehurst and coworkers
7
that aimed to identify genes that de-sensitized lung cancer cells to the microtubule-stabilizing
chemotherapeutic agent paclitaxel, a number of CTA genes were found to be capable
of driving chemoresistance, indicating germline genes contribute to therapeutic resistance.
Not only do these studies demonstrate that germline genes are important in driving
the oncogenic process, it also reveals a new class of therapeutically targetable molecules,
the extent and potential of which remains very poorly explored.
The proposal that a soma-to-germline transition is occurring in human cancers to drive
oncogenic mitotic proliferation of cells in the soma may infer that activation of
a multitude of germline genes is required. However, the evidence to support an extensive
co-activation remains weak. It is possible, even likely, that the activation of one
or a few key regulatory CT genes can contribute to oncogenesis in the absence of extensive
germline program activation. Moreover, it is likely that distinct germline gene functions
serve to contribute to distinct features of tumor progression and survival. While
there are now many detailed questions to be addressed, it is clear that oncogenesis
involves the loosening of the constraints on expression of not only X encoded germline
genes, but also of the large cohort of meiosis-associated genes identified by Feichtinger
and coworkers
3
,
4
that are autosomally encoded. Activation of meiotic functions, including programmed
inter-homolog recombination and reductional chromosome segregation pathways mediated
by centromeric monopolarity, in somatic cells clearly has the potential to disturb
somatic cellular genetic homeostasis and provide the factors to drive the genetic
instability and tumor heterogeneity that is required for oncogenic progression and
therapeutic resistance.