Stem Cells and Cancer: The Exquisite Dance

As many as 20% of cancers or more originate in stem cells. Our bodies are homes to hordes of stem cells, sometimes quiescent, sometimes regenerative, and sometimes proliferating out of control. The female breast is one organ that is amply supplied with stem cells.

"People have long suspected there should be a stem cell population in the human breast gland," said Sigurdsson who is part of the ESF-funded team led by Thorarinn Gudjonsson. A 'virgin' breast, before pregnancy, is very different to a fully functioning, milk-producing breast. With lactation, the breast becomes fully differentiated, and once this stage is over, it involutes. This cycle of proliferation, differentiation and apoptosis also happens in every menstrual cycle and in a more dramatic form during pregnancy. "This caught our attention, and has driven our research," Sigurdsson pointed out.

Breast cancer almost always occurs in the luminal epithelial compartment, which is also where milk is produced. Perhaps it is not surprising then, that stem cells reside in this compartment. In 2002, Thorarinn Gudjonsson, successfully isolated cells from the human breast with stem cell properties.

Gudjonsson immortalised these cells and grew them in three dimensional matrix that mimics the real, living tissue. Biologists have long relied on 2-dimensional cell cultures as the basic tool of their trade. But there is a big difference between a flat layer of cells and culturing cells in three-dimensions. The Icelandic researchers, realizing just how much a cells context matters, used the 3-D cell culture pioneered by Mina Bissell, at the Lawrence Berkeley National Laboratory in California. "We can build up a 3-D breast structure similar to what you have in vivo," says Gudjonsson.

"You can analyse cell-cell interactions and signaling pathways in these cells during morphogenesis and in cancer progression." The Icelandic researchers are now focusing their efforts on how endothelial cells convey signals to stem cells in normal breast formation and in cancer. In collaboration with another Icelandic research team, the Gudjonsson lab is now unraveling the role of tyrosine kinase receptors and their downstream signaling events. Source.

And so we see that stem cells are a two-edged sword in the breast. The same is true in other tissues. Stem cells are vital for regenerative functions, but must be held in check by tumour suppressor genes.

[A tumour suppressor gene,]PTEN functions to decide whether to progress further though the cell cycle or return to a quiescent (G0) state. Disrupting PTEN in stem cells results in more active cycling and a loss of the quiescent pool of stems cells that is necessary for long-term stem cell maintenance.

PTEN can be phosphorylated in response to other signals that modulate its function. The Li Lab's work demonstrated distinct populations of hematopoetic stem cells (HSCs) with phosphorylated and unphosphorylated forms of PTEN, suggesting that PTEN phosphorylation may be a 'sensor' that could help integrate external cues with the HSC quiescence/activation switch.

"Although the primary mutation occurs in stem cells, leading to short-term expansion of normal stem cells, this mutation alone is not enough to support unlimited expansion of either normal or cancer stem cells," said Dr. Li. "A secondary mutation is therefore required to empower the leukemia cells resulting from this mutation to undergo unlimited expansion. Exploring the nature of the secondary mutation, together with the primary mutation in PTEN, can help to understand the self-renewal ability of stem cells and perhaps will identify new molecules that can be targeted to provide effective leukemia treatment without adversely affecting normal stem cells." Source.

Sometimes the tumour suppressor genes are silenced, and if the tumour cells can maintain the silencing of the suppressor genes, the tumours are free to grow. Methylation is one means of gene silencing that tumours take advantage of.

Our cells become cancerous when the normal controls over cell growth and death go awry. This deregulation has traditionally been linked to DNA mutations of single genes or deletion of large sections of the chromosome. However more recently it has become clear that gene silencing in cancer can also occur, in the absence of changes to the DNA sequence: a phenomenon known as 'epigenetics'. DNA methylation is one of the main epigenetic processes.

In cancer, the DNA methylation pattern of many genes changes. However, until now, it was believed that only individual single genes were silenced by methylation. But this is not necessarily the case. "What we've found is that non-methylated genes that reside in a particular suburb near methylated genes are also silenced. Their physical proximity to the methylated genes affects their ability to function. It's a case of being in the wrong neighbourhood at the wrong time", says Assoc. Professor Clark.

The Garvan team developed a new method to scan the entire complement of the 30 000 plus genes - the entire genome - in the cancer tissue samples, which allowed widespread changes to be identified in specific parts of the genome.

They were amazed to find the extent of gene silencing. Assoc. Professor Clark adds: "What we want to do now is determine if these same regions are switched off in other types of cancers". Source.

Given that adult male testicles carry a sizable contingent of stem cells, it is perhaps surprising that testicular cancer is no more common than it is. There is considerable interest in testicular stem cells, and their possible potential in regenerative medicine. Projects are currently underway to learn how to extract and culture testicular stem cells in vitro. The following describes a project to culture specifically the spermatogonial stem cells, although more pluripotent cells are present.

"Our plan is to develop a culture system for spermatogonial stem cells" de Rooij told conference attendees. Although admitting the leap to humans is considerable, the colonised mouse testes are already providing useful insights.

"We'd like to know how to culture human spermatogenic stem cells to restore male fertility after cancer therapy," says Hannu Sariola, from the University of Helsinki in Finland who is also working towards a similar goal.

Bizarrely, a brain cell growth factor also has a powerful influence on spermatogonial stem cells. Glial cell derived neurotrophic factor (GDNF) is also involved in spermatogenesis: levels are high during the neonatal period and drop in adulthood. Indeed, mice that have been genetically manipulated to express high levels of GDNF in the testes produce huge clusters of spermatogonial stem cells. But the risk of cancer is boosted too, so it is not just about turning on the GDNF tap indiscriminately. It must be tightly regulated, Sariola pointed out.

The Dutch researchers are also hunting for the ideal conditions and nutrients that will coax spermatogonial stem cells into becoming sperm. So far, they have found that growth factors GDNF and fibroblast growth factor (FGF) seem to be necessary to enhance cell growth. The team's next move is to transplant monkey and human cells into the mouse testes system. Source.

Such are a few of the many molecular moves of the exquisite dance of the cell. It is not surprising that so many things sometimes go wrong. Rather, it is amazing that so many things go right for so long. But then, that is evolution's doing--we cannot take credit. The things that are coming, well, that is another matter.