Genome Duplication and Cancer

What Is Cancer?

  • Cancer refers to tumors and other neoplasia that are malignant and contain cells that can metastasize to distant locations.
  • Cancer cells proliferate & migrate when & where normal cells do not.
  • Cancer hallmarks are genomic instability and aneuploidy.

How Does Cancer Originate?

  • Cancer originates from genetic mutations that are either inherited or result from environmental factors.
  • Cancer originates from 'stem cells' that retain their ability to proliferate indefinitely without losing their ability to initiate a cancer. All tumor cells proliferate under conditions where normal cells do not, but only 'cancer stem cells' can initiate a tumor de novo.

How is Cancer related to DNA replication?

Cancer cells exhibit three characteristics that are linked directly to genome duplication: genome instability, unregulated cell proliferation, and resistance to apoptosis.

Genome stability depends on the number of active replication origins per genome. Low origin densities produce fewer replication forks that must travel greater distances, thus increasing the probability that forks will stall or suffer damage. Conversely, high origin densities increase the possibility of DNA damage during the initiation process, and the possibility that too many forks will trigger a DNA damage response. 

Unregulated proliferation means that cancer cells duplicate their genome much more frequently than normal cells do, and therefore increase the risk of genome instability and genetic mutations.  Unregulated proliferation results from increased sensitivity of cancer cells to mitogenic stimuli and decreased sensitivity to contact inhibition. Cancer cells continue to proliferate under nutritional conditions in which normal cells complete cell division and then go into a quiescent state termed ‘G0-phase’. In addition, cancer cells continue to proliferate when they come into contact with other cells whereas normal cells stop proliferating when cell to cell contacts are made.

Apoptosis (programmed cell death) is a physiological response to excessive stress. Normal cells have multiple checkpoints that respond to stress by preventing further initiation events during S-phase, stabilizing replication forks until they are repaired, and preventing the onset of mitosis until DNA replication is completed. If the stress cannot be relieved (e.g. DNA damage that cannot be repaired within a few hours), then DNA damage response pathways trigger apoptosis.  Cancer cells lack several of these checkpoints, which means that mutations are more easily generated and restrictions on genome duplication more easily ignored. The tumor suppressor genes Retinoblastoma (Rb) and TP53 are the cell proliferation control genes whose activities are most frequently altered in cancers (1). Rb regulates expression of a large number of genes that are required for S-phase. Cell cycle exit depends upon turning off these genes. TP53 is a transcription factor that is induced by DNA damage, hypoxia or oncogene activation. TP53 regulates expression of genes that either arrest cell proliferation or trigger apoptosis.

We have made three discoveries that provide proof-of-principle that cancer cells can be induced to undergo apoptosis under conditions where normal cells continue to proliferate.  

  1. We have identified 42 genes that restrict genome duplication to once per cell division by preventing either DNA re-replication or unscheduled endoreplication. All 42 genes participate in one or more of eight cell cycle events. Seventeen of them have not been identified previously in this capacity. Remarkably, 14 of the 42 genes have been shown to prevent aneuploidy in mice. Moreover, suppressing a gene that prevents EDR increased the ability of the chemotherapeutic drug Paclitaxel to induce EDR, suggesting new opportunities for synthetic lethalities in the treatment of human cancers (Vassilev et al., Oncotarget, 2016). 
  2. One of these genes encodes geminin, a protein unique to multicellular animals that prevents DNA re-replication, and that also appears to have roles in modulating gene expression. We discovered that geminin is essential at the beginning of mammalian development to prevent DNA re-replication-dependent apoptosis in pluripotent cells when they undergo self-renewal, but that once they have differentiated into specific cell types, geminin is no longer essential for viability, although it continues to contribute to preventing DNA re-replication induced DNA damage (Huang et al., Stem Cells, 2015).  Since embryonic stem cells (ESCs) become cancer stem cells when located at ectopic sites, by differentiating into teratomas and teratocarcinomas, inhibition of geminin function might prevent formation of germ cell neoplasia without harming normal cells. 
  3. We discovered that siRNA suppression of geminin (a specific inhibitor of CDT1) arrested proliferation only of cells derived from cancers by inducing DNA re-replication and DNA damage that spontaneously triggered apoptosis. None of these effects were detected either in cells derived from normal human tissues or in cells immortalized by a viral oncogene. (Zhu & DePamphilis, Cancer Res., 2009). Therefore, initiating DNA replication in some cancer cells is limited solely by regulating the level of CDT1 activity with geminin, whereas noncancer cells contain additional safeguards that prevent DNA re-replication. Thus, inhibition of geminin activity could be used to selectively kill cancer cells without harming normal cells.
  4. We are currently extending these discoveries by exploring ways in which to selectively target a specific gene that results in killing a specific cancer stem cell or a specific cancer without harming normal cells.
top of pageBACK TO TOP