The Power of Flower

 

We know we don’t ‘understand cancer’ — for if we did we would at least be well on the way to preventing the ten million annual deaths from these diseases and perhaps even stymieing their appearance in the first place. But at least, after many years of toil by thousands of curious souls, we might feel brave enough to describe the key steps by which it comes about.

Here goes!

Our genetic material, DNA, carries a code of four different units (bases) that enables cells to make twenty-thousand or so different types of proteins. Collectively these make cells — and hence us — ‘work’. An indicator of protein power is that we grow from single, fertilized cells to adults with 50 trillion cells. That phenomenal expansion involves, of course, cells growing and dividing to make more of themselves — and, along the way, a bit of cell death too. The fact that there are nearly eight billion people on planet earth testifies to the staggering precision with which these proteins act.

Nobody’s perfect

As sports fans will know, the most successful captain in the history of Australian rugby, John Eales, was nicknamed ‘Nobody’ because ‘Nobody’s perfect’. Well, you might care to debate the infallibility of your sporting heroes but when it comes to their molecular machinery, wondrous though it is, perfect it is not.

Evidence: from the teeming eight billion there emerges every year 18 million new cancer cases (that’s about one in every 444). And cancers are, of course, abnormal cell growth: cells growing faster than they should or growing at the wrong time or in the wrong place — any of which means that some of the masterful proteins have suffered a bit of a malfunction, as the computer geeks might say.

How can that happen?

Abnormal protein activity arises from changes in DNA (mutations) that corrupt the normal code to produce proteins of greater or lesser activity or even completely novel proteins.

These mutations may be great or small: changes in just one base or seismic fragmentation of entire chromosomes. But the key upshot is that the cell grows abnormally because regulatory proteins within the cell have altered activity. Mutations can also affect how the cell ‘talks’ to the outside world, that is, the chemical signals it releases to, for example, block immune system killing of cancer cells.

Clear so far?

Mutations can change how cells proliferate, setting them free of normal controls and launching their career as tumour cells and, in addition, they can influence the cell’s environment in favour of unrestricted growth.

The latter tells us that cancer cells cooperate with other types of cell to advance their cause but now comes a remarkable discovery of a hitherto unsuspected type of cellular collaboration. It’s from Esha Madan, Eduardo Moreno and colleagues from Lisbon, Arkansas, St. Louis, Indianapolis, Omaha, Dartmouth College, Zurich and Sapporo who followed up a long-known effect in fruit flies (Drosophila) whereby the cells can self-select for fitness to survive.

Notwithstanding the fact that flies do it, the idea of a kind of ‘cell fitness test’ is novel as far as human cells go — but it shouldn’t really surprise us, not least because our immune system (the adaptive immune system) features much cooperation between different types of cell to bring about the detection and removal of foreign or damaged cells.

Blooming science

So it’s been known for over forty years that Drosophila carries out cell selection based on a ‘fitness fingerprint’ that enables it to prevent developmental errors and to replace old tissues with new. However, it took until 2009 before the critical protein was discovered and, because mutant forms of this protein gave rise to abnormally shaped nerve cells that looked like bunches of flowers, Chi-Kuang Yao and colleagues called the gene flower‘.

Cells can make different versions of flower proteins (by alternative splicing of the gene) the critical ones being termed ‘winner’ and ‘loser’ because when cells carrying winner come into contact with cells bearing loser the latter die and the winners, well, they win by dividing and filling up the space created by the death of losers.

The effect is so dramatic that Madan and colleagues were able to make some stunning movies of the switch in cell populations that occured when they grew human breast cancer cells engineered to express different version of flower tagged with red or green fluorescent labels.

Shift in cell populations caused by two types of flower proteins. 

Above are images at time zero and 24 h later of co-cultures of cells expressing  green and red proteins (losers and winners). From Madan et al. 2019.

Click here to see the movie on the Nature website.

Winner takes almost all

The video shows high-resolution live cell imaging over a 24 hour period compressed into a few seconds. Cells expressing the green protein (hFwe1 (GFP)) were co-cultured with red cells (hFwe2 (RFP)). Greens are losers, reds winners. As the movie progresses you can see the cell population shifting from mainly green to almost entirely red, as the first and last frames (above) show.

How does flower power work?

Flower proteins form channels across the outer membrane of the cell that permit calcium flow, and it was abnormal calcium signalling that caused flowers to bloom in Drosophila nerves. It would be reasonable to assume that changes in calcium levels are behind the effects of flower on cancer cells. Reasonable but wrong, for Madan & Co were able to rule out this explanation. At the moment we’re left with the rather vague idea that flower proteins mediate competitive interactions between cells and these determine whether cells thrive and proliferate or wither and die.

Does this really happen in human cancers?

Madan and colleagues looked at malignant and benign human tumours and found that there was more ‘winner’ flower protein in the former than the latter and that ‘loser’ levels were higher in normal cells next to a tumour than further away. Both consistent with the notion that tumour cells express winner and this induces loser in nearby normal cells leading to their death. What’s more they reproduced this effect in mice by transplanting human breast cancer cells expressing winner.

So there we are! After all this time a variant on how cancer cells can manipulate their surroundings to promote the development of tumours. Remarkable though this finding is, in a way that is familiar it’s just the beginning of this story. We don’t know how flower proteins work in giving cancers a helping hand and we don’t know how effective they are. Until we answer those questions it would be premature to try to come up with therapies to block their effect.

But it is a moment to sit back and reflect on the astonishing complexity of living organisms and their continuing capacity to surprise.

Reference

Madan, E. et al. (2019). Flower isoforms promote competitive growth in cancer. Nature 572, 260-264.

Yao, C-K., et al., (2009). A synaptic vesicle-associated Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis. Cell 138, 947–960.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s