While the presence of germ cell proteins in malignancies is well documented, the reason why they are expressed is not clearly understood. Theories on germ cell protein expression can be grouped into three general categories including (1) accidental/nonfunctional, (2) accidental/functional, and (3) programmed/functional.
The first is an accidental activation of germ cell-specific genes, which do not provide any functional benefit to the cancer cell. This scenario would include processes like widespread epigenetic regulation that would turn on germ cell genes secondarily but without any benefit to the cell. The most noted epigenetic controls in germ cell gene expression appear to be DNA methylation and posttranslational histone modifications [11
The second category consists of the accidental activation of germ cell genes, but with a functional benefit to the cancer cells. By providing a benefit, the cancer cells that express these germ cell genes may survive and thrive better than those without expression thereby expanding the population expressing beneficial germ cell proteins.
Lastly, the expression of germ cell proteins may be programmed into the cell to be activated under certain conditions. These conditions could include hypoxia, lack of nutrients, and oxidative stress. Primitive organisms, like yeast, tend to increase genetic recombination when they experience such stresses in order to create new phenotypes that may be better suited for the environment [9
]. A recent study by Forche et al. found a correlation between loss of heterozygosity in Candida Albicans and the degree of stress the yeast was exposed to, suggesting increased levels of gene rearrangement [8
]. Due to overgrowth of the local blood supply, a fraction of cancer cells would be expected to be hypoxic and possibly nutrient deprived. An evolutionary conserved programmed response to the lack of oxygen and nutrients could lead to the activation of germ cell proteins, causing genetic recombination, and genomic instability, similar to that seen in yeast, allowing cancer cells to adapt to the environment and become more suited to thrive in adverse conditions.
In all three scenarios it would be expected that there would be differential expression of germ cell proteins in the tumor mass as the cancer progresses. Indeed, germ cell proteins are often heterogeneously expressed. Specifically, heterogeneity has been noted in the expression of SSX, GAGE, and NY-ESO1 [45
]. This heterogeneity suggests the germ cell proteins are differentially regulated in the tumor cells. Evidence has been found for an increase in germ cell protein expression with tumor progression. A study by Barrow et al. found that both antigens MAGE-A1 and MAGE-A4 showed an increase in expression throughout disease progression [25
]. Additionally, MAGE-A3 expression reveals a correlation with disease progression [37
]. These patterns suggest that germ cell protein expression may be playing a role in tumor progression. The increase in expression may suggest that the germ cell phenotype confers adaptations more suitable for survival in adverse conditions. If these germ cell-specific genes are being turned on as a programmed response to stressors, their function is likely significant to survival of the cancer cells. Therefore, disrupting this function may decrease the ability of cancer cells to adapt and thrive under stressful conditions.
There is increasing evidence that germ cell pathways can be activated and may play a role in tumorigenesis. Hypoxic stress has been noted to induce germ cell protein expression in rat kidney fibroblasts, suggesting that hypoxia by itself may be enough to turn on some of these pathways [48
]. The germ cell regulatory protein, PLU1 (JARID1B), has been shown to mark a subpopulation of melanoma tumor cells required for continuous tumor growth [49
]. Further an association between germ cell gene expression and brain tumors in Drosophila
has recently been identified [50
]. Knock-down experiments of several of the germ cell proteins revealed that they played a critical role in tumor growth [50
]. Together these studies support the idea that germ cell pathways may be activated due to stress or other means and that these proteins then functionally benefit the malignant state.
Although it is possible that germ cell protein expression is accidental/nonfunctional in cancer, given the association of upregulation with hypoxia and role in brain tumor development, it is more likely that expression of these pathways is programmed and functional in tumor development.