Meiosis-like Functions in Oncogenesis: A New View of Cancer

Abstract

Cancer cells have many abnormal characteristics enabling tumors to grow, spread, and avoid immunologic and therapeutic destruction. Central to this is the innate ability of populations of cancer cells to rapidly evolve. One feature of many cancers is that they activate genes that are normally associated with distinct developmental states, including germ cell–specific genes. This has historically led to the proposal that tumors take on embryonal characteristics, the so called embryonal theory of cancer. However, one group of germline genes, not directly associated with embryonic somatic tissue genesis, is the one that encodes the specific factors to drive the unique reductional chromosome segregation of meiosis I, which also results in chromosomal exchanges. Here, we propose that meiosis I–specific modulators of reductional segregation can contribute to oncogenic chromosome dynamics and that the embryonal theory for cancer cell growth/proliferation is overly simplistic, as meiotic factors are not a feature of most embryonic tissue development. We postulate that some meiotic chromosome-regulatory functions contribute to a soma-to-germline model for cancer, in which activation of germline (including meiosis) functions drive oncogenesis, and we extend this to propose that meiotic factors could be powerful sources of targets for therapeutics and biomonitoring in oncology. Cancer Res; 77(21); 5712–6. ©2017 AACR.

A pseudo-meiotic centrosomal function of TEX12 in cancer

“…This likely represents a role of TEX12 that is favoured when it cannot participate in SC assembly, which may be analogous to the formation of chromatin-free SYCP1 polycomplexes in the absence of an SC in meiotic and somatic cells 32,33 . We therefore propose that, in keeping with the mechanism of other meiosis-specific genes in cancer 3,4 , the centrosomal role of TEX12 in cancer cells may represent a previously overlooked pseudomeiotic function.…”

“…Cell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes 1,2 . The many meiosisspecific genes involved in these processes also constitute a latent toolbox of chromosome remodelling and recombination factors that may be exploited through aberrant expression in cancer 3,4 . Here, we report that TEX12, a structural protein involved in meiotic chromosome synapsis [5][6][7] , is aberrantly expressed in human cancers, with high TEX12 levels correlating with poor prognosis.…”

Meiotic gene activation in somatic and germ cell tumours

“…Germ line gene activation, including meiotic genes, appears to be a common feature in a range of human neoplastic conditions (McFarlane et al ., , ; McFarlane & Wakeman, ). If applied to mitotically proliferating cells, the specific molecular mechanisms driving reductional segregation in gametogenic meiosis I could be considered to be deleterious and potentially highly oncogenic.…”

“…Examples include the genesis of DSBs, the modulation of inter‐homologue repair of DSBs that could drive loss of heterozygosity, the alteration of the transcriptional landscape, the epigenetic activation of recombination hot spot loci and the monopolar orientation of sister chromatid centromeres. Evidence is starting to emerge that meiosis‐like activities mediated by unscheduled activation of meiotic genes do indeed contribute to oncogenesis, but there are some unexpected ways in which these activities make their contribution, challenging intuitive hypotheses for roles of meiotic gene activity in cancer cells (McFarlane & Wakeman, ). This is particularly apparent when applied to GC tumours where activation of meiosis‐specific genes might be taken to imply meiotically primed cells are attempting a programmed entry into meiosis, albeit a flawed one (Jørgensen et al ., ).…”

“…Yet another possibility is that most GC tumours derive from pre‐meiotic PGCs, in which meiotic factors are prematurely and unscheduled activated through defects in gene regulatory mechanisms as observed in other cancers, rather than through a defect in the switching between the mitotic and meiotic modes. As discussed in the previous section, many tumours exhibit aberrant expression of meiotic genes, in particular meiotic chromosome regulators (and germ line genes in general), and oncogenic links have been shown (McFarlane & Wakeman, ). Either way, these cells do not or cannot initiate a full meiotic programme, which is supported by the fact that varying and contradicting expression patterns of meiotic genes in GC tumours, cell lines and/or pre‐malignant GCNIS have been reported (Adamah et al ., ; Jørgensen et al ., ) (Fig.…”