by ecancer reporter Janet Fricker

Cooperation between different tumour clones may be needed for successful establishment of metastasis, suggest two separate studies published this week in Nature and Nature Communications.

Despite the clinical importance of metastases, which account for 90% of cancer related deaths, little is known about the principles governing the dissemination of cancer cells to distant organs.

Traditionally, it was thought that a single cell or ‘seed’ was responsible for the generation of metastases, but more recently studies have indicated that ‘multiple seeds’ from different origins cooperate in the establishment of metastases.

Indeed, recent mouse models of cancer have demonstrated the existence of polyclonal seeding, and the interclonal cooperation between multiple subclones.

In the first study, Steven Bova from the University of Tampere, Finland, and colleagues, undertook whole genome sequencing on 51 metastases and primary tumours from 10 patients who had died from prostate cancer.

The team used tumours collected over 20 years.

They found that two or more subclones had seeded the same site, (a phenomenon known as polyclonal seeding) in at least one metastasis in five of the 10 patients.

Furthermore, they showed multiple subclones were shared between clones at the different sites, suggesting that these subclones might ‘functionally cooperate’ with each other to promote metastatic progression.

The investigators also showed that eight of the 10 patients showed metastatic ‘cross-seeding’ where the clones within a metastasis originated from another metastatic site, rather than from the primary tumour.

“Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer,” write the authors.

Such observations, suggest the authors, support the ‘seed and soil’ hypothesis in which rare subclones develop metastatic potential within the primary tumour rather than the theory that metastatic potential is a property of the primary tumour as a whole.

In a second paper Matthew Hong, from the University of Melbourne, and colleagues analysed 26 samples taken from four prostate cancer patients who died of the condition, and again found evidence of cross-seeding.

Further larger cohort studies, they write, are required to assess the incidence of these findings in the general advanced prostate cancer population.

By ultra-deep sequencing end-stage blood taken at the time of death, the team detected both metastatic and primary tumour clones, several years after surgical removal of the prostate.

“This indicated that circulating tumour cells with the potential to seed metastases persist in the long term,” writes Michael Shen (Columbia University Medical Center, New York) in an accompanying News & Views article.

“The heterogeneous (mixed) clonal composition of the metastases described in these two reports raises the issue of whether clonal heterogeneity might be intrinsic to the metastatic process,” writes Shen.

Metastasis, he goes on to suggest, may be facilitated by two or more distinct tumour subclones cooperating to promote their mutual growth and survival.

“If so, it is attractive to speculate that disseminated single cells could remain dormant until reawakened by interaction with a cooperative metastatic cell arriving at the same secondary site,” he writes, adding that understanding the signalling pathways that mediate such clonal cooperativity may lead to effective therapies using drugs that target these pathways.

Reference

G Gundem, P Van Loo, B Kremeyer, et al. The evolutionary history of lethal metastatic prostate cancer. Nature.

M Hong, G Macintyre, D Wedge, et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nature Communications.

M Shen. 'The complex seeds of metastasis.' Nature.