Following cancer’s journey

01 April 2015
By David Wedge

Subclonal structure within 10 metastatic lethal prostate cancers. Subclones shown as phylogenetic trees and oval plots. Patients with polyclonal seeding (A34, A22, A31, A32 and A24) on right. <strong><br>Click to view larger image</strong><br>Credit: DOI:10.1038/nature14347

Subclonal structure within 10 metastatic lethal prostate cancers. Subclones shown as phylogenetic trees and oval plots. Patients with polyclonal seeding (A34, A22, A31, A32 and A24) on right.
Click to view larger image

Credit: DOI:10.1038/nature14347

In my last post I explained how the numerous different tumour cells found in prostate and other cancers can make it difficult for clinicians to decide on appropriate therapy. In this post, I will explore how this heterogeneity in primary tumours evolves over time, how cancer progresses as tumours spread to other organs (metastasise) and how metastatic tumours respond to treatment.

In a study published in Nature today, we sequenced the whole genomes of 46 metastatic tumours and five primary prostate tumours from 10 men. As cancer cells multiply and spread, they acquire mutations. By identifying these mutations across multiple metastases from the same man, we were able to track the movement of these cells throughout the body.

As I described in the previous post, cancers are made up of separate populations of genetically related cells, which we call subclones. The cells within each of these subclones are descended from a single cell that had a set of mutations in its DNA, or ‘genotype’, that gave it a growth or survival advantage within its environment.

We were particularly interested in the interaction between the genotype and the environment. The environment is made up of many different factors, which change over time. When cancerous cells first appear, their environment is constituted primarily of normal, healthy cells and they have to compete with these cells for energy, space and resources.

As a tumour grows, cells within its interior no longer directly interact with normal cells and they compete mainly with other cancerous cells. The environment changes again if cancer cells escape into the bloodstream and metastasise, seeding tumours in new tissues. The environment may also change as a result of exposure to chemicals, including the chemotherapeutic and targeted drugs that are used to treat cancers.

What did we find?

  • Metastases within a single patient arose from a single cell
  • This is interesting because, as I described in my last post, prostate cancers are commonly made up of several genetically distinct tumours.
    We do not know whether the metastases we studied were derived from multifocal primary tumours but, if they were, it appears that only one region of each primary tumour, with a specific genotype, was able to escape into the bloodstream and to metastasise.

  • The malfunctioning of tumour-suppressor genes is an early event that enables tumours to grow
  • A set of genes, known as tumour suppressors, are known to prevent or inhibit the development of cancer. These genes can be prevented from functioning by mutations or deletions in DNA. Where we saw these mutations they were almost always found in all of the samples taken from one patient, suggesting that they occurred early in cancer development, before metastatic spread.

  • Male sexual development hormones are hijacked by metastatic tumours
  • The region of DNA that encodes for the androgen receptor gene, which is important for male sexual development at birth and puberty, is found on the X-chromosome. We found that all metastases had replicated this region of the chromosome, resulting in increased production of the corresponding protein.

    Prostate cancers are dependent on the androgen receptor to stimulate growth and all of the patients had been treated with androgen deprivation therapy to inhibit this growth. It is fascinating that the response of the metastases was, in all cases, to ramp up the production of the androgen receptor in response to therapy rather than to acquire new mutations that might provide an alternative route to unrestrained growth. This response was seen even though the tumours had spread from the prostate to other parts of the body.

  • Tumours in other organs had cells from two or more prostate cancer subclones
  • Most excitingly of all, from our analysis of the subclones we could see that several of the metastases were made up of mixtures of subclones, with similar sets of subclones found in many different metastases.

    It is usually assumed that metastases grow from a single tumour cell. However, if the metastases had grown from a single cell, it would be possible to represent all subclones in each metastasis in a single family tree.

    Since we see multiple subclones spread across multiple metastases, there must have been seeding of two or more cells between metastatic sites.

    Our findings raise a number of further questions:

    • Are the subclones competing with each other or are they actually cooperating, as suggested by the high frequency of polyclonal seeding?
    • Does polyclonal seeding occur in other tumour types and in earlier-stage cancers?
    • Do the multiple cells that seed a metastasis travel through the bloodstream as a single clump or do they travel separately?

    We hope to investigate these questions in future studies.

    This research was funded by Cancer Research UK

    David Wedge is a Senior Staff Scientist in the Cancer Genome Project at the Wellcome Trust Sanger Institute, working on heterogeneity and evolution within prostate and other cancers.

    References

    • Cooper CS, Eeles R, Wedge DC, Van Loo P, et al (2015). Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nature GeneticsDOI:10.1038/ng.3221

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