How does a cancer start?

As is my practice, my starting point is Dr Robert Weinberg[i]. In his outstanding textbook, The Biology of Cancer, he writes:

“The process of tumor formation is a complex one of multiple steps involving multiple alterations of cells and their physiologic control mechanisms. The complexity of this process is reflected in the long time periods required for most human cancers to develop”.

It is also usually assumed that metastasis, the spread of a cancer, occurs late in this process.

This is the usual understanding of how a cancer starts or, as Weinberg concedes, how most cancers start.

….. but it is not always like that.

A recent discovery is that some cancers develop very quickly, and can even spread before the tumour is detectable. Such cancers are considered to be "Born to be Bad” (see e.g., Collins[ii]).

How does this happen? And what do these cancers look like?

We turn to the case of Zarah.

Zarah

Zarah was 38 when she was diagnosed with an invasive bladder cancer. Her cancer story is described and analysed in a book by Henry Scowcroft [iii].

Henry, her boyfriend, was a science reporter with Cancer Research UK. He therefore had the knowledge and experience to thoroughly investigate and document her cancer. Moreover, his occupation gave him access at the time to leading cancer researchers and to the latest genetic technologies. All this allows a deep insight into the nature of her cancer.

Hers was not a typical bladder cancer. Bladder cancer is a disease occurring most commonly among older people (mainly men), often with a history of smoking, and whose tumour DNA (due to decades of exposure to toxic, DNA-damaging carcinogens as they drain through the bladder) is often riddled with mutational spelling mistakes.

But Zarah was in her 30s, was at worst an occasional social smoker, and her cancer was relatively low in mutations.

Furthermore, her cancer was high grade and late stage, and at diagnosis had already spread to an extent that it was unlikely to be cured. What we call a “Bad” cancer in our website.

How did her cancer start?

Zarah’s cancer was driven by two vital early losses in her tumour genes:

         i.            First of all, one of her bladder cells developed instability in the cell division process.

There was a loss of the ‘go/no-go’ control switch in the cell division process of one of the cells in her bladder wall. This made the cells in the developing clone impatient; hurriedly attempting to divide, often even before their chromosomes were fully duplicated and aligned.

The resulting cells also developed a stutter in the cell division process, every so often repeating short sections of genetic information.

So, there was early instability in the cell division process, which increased the error rate in the division process.

       ii.            But there was still a guardian in place …..

These cells thus became reliant on molecular control systems programmed to fix errors arising in cell division.

And when the mother cell made too great an error, an internal guardian stood in place to trip the alarm and cause the cell to destroy itself; a backstop commonly known as the guardian of the genome[iv].

Thus, Initially, her cells were protected against the instability.

     iii.            ….. until there wasn't - the second early loss

During another hurried round of division, as the mother cell’s replication machinery reached the segment of the chromosome that bore the guardian’s DNA code, it made a second unforced error … and the guardian gene was lost.

There was now instability in the cell division process without any backstop protection, leading to a significant increase in the mutation rate in the resulting clone.

And then there was a third key event ….  a CRASH:

As one of the resultant cells geared up to divide, something snapped. Rather than the chromosomes separating equally – 46 for each offspring – all 92 in the dividing cell were pulled to one end of the cell, before the drawstring was pulled tight.

The resulting cell had double the normal number of chromosomes.

This was essentially a crash, what is known as a genome doubling. Zarah’s tumour now not only had an unstable cell, but one which also had double the amount of DNA ….. a major evolutionary accelerator in the newly emerging clone.

Bottom line: there was now what Arney[v] has termed a ‘monster cell’ - one with both genetic instability as well as high evolutionary capability.

So, what did her cancer cells look like?

What did the resulting tumour cells look like? Here I quote from Scowcroft:

"When Charlie’s team[vi] looked at the overall state of Zarah’s tumour’s chromosomes, it was not a pretty picture. Whole sections, containing scores of vital genes, had been duplicated, often many times over. Other chunks of DNA were missing entirely, deleting vital genes from the cell’s sophisticated and finely balanced control systems. So, rather than typos in individual words, Zarah’s tumour was characterised by scores of copy-and-paste errors, in entire paragraphs and pages of her personal book of life. This suggests that, from relatively early in its development, her tumour was driven, at least in part, by internal forces of instability – of erroneous repair and replication – rather than by external assault."

All in all, it was a mess …. or as I read in an article many years ago (but did not understand at the time), “it looks like someone set off a bomb in the nucleus.”[vii]

So, what drives a ‘Born to be Bad’ cancer?

As we have said, ‘Born to be Bad’ cancer is a recent discovery and the understanding of such cancers has a long way to go. But the research to date suggests the following key drivers:

1.       Early instability, especially with respect to pathways that control cell division, structure and internal messaging.

·       Recall Zarah’s vital two early losses (“there was now instability in the cell division process without any backstop protection”).

·       And then there is the statement in the description in the previous section: “This suggests that, from relatively early in its development, her tumour was driven, at least in part, by internal forces of instability”.

2.       Large-scale genomic damage, especially to chromosomes – as is well-reflected in the description of what Zarah’s cancer cells looked like.

All very far removed from the more usual process of a “sequence of mutations over a very long time”.

Zarah’s Cancer Journey

Despite being young when diagnosed - as well as having excellent doctors, treatment and scientific support - Zarah died just 9 months after diagnosis.

She had a good initial response to chemotherapy.

Followed by period where there her scans showed no evidence of disease.

But, arising from the genetic instability, her tumour was heterogeneous and consisted of four subclones.

And one of these subclones, although very significantly smaller after treatment, had survived the treatment.

And this surviving subclone then came roaring back and took her life before her treatment could be adapted.

Every death from cancer is a tragedy, a body turning on itself. And is especially so when it is someone so young. In his book, Henry also speaks of the human side of this tragedy. A story of ups and downs, hope and despair. And ultimately, a brave but, still all too frequent, sad journey.

[i] Dr Weinberg is Director of the Ludwig Center for Molecular Oncology at MIT, the Daniel K. Ludwig Professor for Cancer Research within MIT’s Department of Biology and a founding member of the Whitehead Institute for Biomedical Research. The quote is from his 2014 textbook The Biology of Cancer.

[ii] Are Some Tumors Just ‘Born to Be Bad’? NIH Director's Blog, Posted on May 22nd, 2018 by Dr. Francis Collins

[iii] Zarah’s story is told in the book by Henry Scowcroft Cross Everything: A personal journey into the evolution of cancer.

[iv] This is one of the most important cancer genes called p53, commonly called the ‘guardian of the genome’. An excellent and readable account can be found in the book: p53: The Gene that Cracked the Cancer Code by Sue Armstrong.

[v] This term is taken from the book Rebel Cell: Cancer, Evolution and the Science of Life by Dr Kat Arney, who titled one of her chapters “Selfish Monsters”.

[vi] Here, Scowcroft is referring to Prof. Charles Swanton, a British physician scientist specialising in oncology and cancer research, with a special focus on how cancers evolve. Scowcroft new Swanton from his work at Cancer Research UK, and consulted Swanton’s expertise and technologies frequently during the course of Zarah’s illness.

[vii] Untangling the Roots of Cancer by W. Wayt Gibbs, Scientific American, 2008