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C O L O R E C TA L C A N C E R

Does early metastatic seeding
occur in colorectal cancer?
Alessandro Magrì and Alberto Bardelli
During the metastatic process, cancer cells spread from the primary tumour
to distant organs. Although metastases are the primary cause of cancer
mortality, the dynamics of the metastatic process remain largely unknown.
A new study suggests that during colorectal cancer progression, metastatic
seeding might occur before clinical detectability.
Refers to Hu, Z. et al. Quantitative evidence for early metastatic seeding in colorectal cancer. Nat. Genet. 51, 1113–1122(2019).

When a tumour is confined to the organ
where it has emerged, such as the breast or
the intestine, treatment with surgery is highly
effective and often curative. However, whenneoplastic cells have already spread to a site
distant from the one where they originatedthe disease is often hard to control. Colorectal
cancer (CRC) is the third most common cancer and half of all patients with CRC willdevelop metastases1. CRC is driven by evolutionary processes and develops through aseries of stages that have been elucidated ingreat detail. These stages include dysplasia ofthe mucosae followed by the formation of adenomas (polyps), which can progress further tomore aggressive stages and ultimately to theformation of metastases often to the liver,lung and peritoneum, and less frequently toother body sites such as bone and the brain2.
The timing and molecular determinants ofthe metastatic process in CRC are still under
debate, but it is generally believed that multiple years, or even decades, are required to proceed from the adenoma stage to the formationof liver metastases3.
In a new study published in Nature Genetics,
Hu and colleagues4 hypothesized that CRC
cells depart the primary tumour extremely
early, when the disease is clinically undetectable with current methodologies. They postulate that some CRCs are ‘born to be bad’— that is, the invasive and metastatic potential of a subset of CRCs is prespecified either
genetically or epigenetically as has been previously suggested5. To test this possibility, theauthors performed whole-exome sequencing

on 118 samples from 23 patients with meta­
static CRC who had developed metastasesin the liver, lung or brain. Multi-region sequen­cing was performed on the primary tumourand paired metastasis to build phylogenetictrees. Using sophisticated computational
methods, the researchers generated patientspecific detailed genetic maps of clonal andsubclonal evolution occurring in the primary
tumours and matched metastases.
In agreement with previous literature,
the study shows that genomic divergence
between the primary tumour and the metastasis is relatively low4. Indeed, more than 70%
of high-frequency somatic single-nucleotide
variants were shared between the primary
tumour and the metastases. Genomic alterations commonly occurring in CRCs, such as
mutations in APC, KRAS, TP53, SMAD4 andTCF7L2, were also highly concordant between
primary tumour and metastasis pairs. Of relevance, the study found that some mutations inSYNE1 and APOB genes tended to be ‘private’(that is, they occurred mainly in the primary
tumour or the metastasis). Furthermore, gene
amplification in PIK3CA, GNAS, SRC, FXR1,MUC4, GPC6 and MECOM seemed to be
specific to metastases.
The most innovative section of the study
is the phylogenetic analysis of CRC evolution, which indicated early divergence of themetastatic lineages4. Using an inference algorithm called SCIMET (spatial computational
inference of metastatic timing) the authors
simulated the timing of when the metastasis
originated from the primary tumour or other

Nature Reviews | GastRoEntERology & HEpatology

lesions. They assumed that CRC initiates froma single founder cell and concluded that themetastasis is seeded by a random single cellfrom the periphery of the tumour when it isvery small (<1 cm3 in volume). The numberof mutations private to the metastasis correlated positively with the timing of dissemination, and subclonal events occurred more
frequently than clonal events in metastases,suggesting that CRC dissemination is an early
event. According to the SCIMET algorithm,
the first metastatic seeding occurred very earlyin >80% of patients when the primary tumour
was below the limits of clinical detectability(Fig. 1). To confirm the findings, Hu et al.4 used
an independent cohort, the MSK-Impact andGENIE public databases which include >2,000clinically annotated CRC cases6. This analysis
showed that ~90% of patients with metastatic
CRC exhibited subclonal selection consistent
with the metastatic clone having a selective
growth advantage. By contrast, only 33% ofpatients with early-stage CRC (stages I–III)
exhibited subclonal selection. Interestingly,
43% of distant metastases evolved neutrally,reflecting the high fitness of the metastatic
initiating clone.
The results of Hu et al.4 are consistent withfindings from a previous study which reported
that private mutation patterns in CRCs might
be a marker of early cell movement and of invasive and metastatic potential5. In that study,
early abnormal cell movement was foundin 9 of 15 invasive ‘born to be bad’ CRCs but innone of four benign adenomas5. The work by
Hu and colleagues4 takes another step forward
in reporting that alterations in a subset of genes(such as TCF7L2, AMER1 and PTPRT) seemto be metastasis-specific, suggesting that they
are involved in driving the metastatic process.
Given that PTPRT encodes an enzyme, if theseobservations are confirmed, PTPRT could act
as a biomarker and should be prioritized as atherapeutic target.
The work by Hu et al.4 concludes that inCRC, metastatic seeding occurs very earlyin the majority of cases, when the neoplastic
mass comprises <106 cells, or even fewer.
According to the authors’ estimates, as few as
105 cells (~0.001 cm3 in volume) can initiate theCRC metastatic process.
As highlighted by the authors, such asmall mass is undetectable with current clinical methods. However, and in apparent conflict with their findings, sigmoidoscopy andNews & Views
AdenocarcinomaEarly
adenoma Tumourcells(<1 cm3)

Invasiveadenocarcinoma

Lateadenoma

at providing accurate molecular profilesof adenomas and other intestinal lesions10.
If ‘born to be bad’ biomarkers can indeed
be detected in the blood, they would be
extremely valuable for identifying individuals
at high risk of developing aggressive forms ofCRC. This population could receive ad hoc
adjuvant strategies such as aggressive chemotherapy to restrict or eliminate the risk of earlymetastatic dissemination.
Alessandro Magrì1,2 and Alberto Bardelli

Blood vesselCirculation*

1,2

Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy.

1

Department of Oncology, University of Torino,Candiolo, Italy.

2

Early metastatic
dissemination‘Born to be bad’colorectal cancers?

Early detection
by liquid biopsy

Fig. 1 | Early metastatic seeding in a subset of CRCs. A fraction of ‘born to be bad’ colorectal
cancers (CRCs) might carry unique and intrinsic biological traits conferring invasive and metastatic
potential before when metastasis was previously considered to occur in the progression of CRC.
Identification of these tumours using blood-based assays would be clinically valuable.

colonoscopy are highly successful at detecting
early CRC lesions (adenomas) and are currently routinely applied in screening protocols7,8. Multiple studies have shown that thedetection and removal of adenomas is very
effective and reduces CRC mortality. Most
individuals in whom an adenoma is detected
and removed during routine colonoscopy do
not develop localized or metastatic CRC7,8. If
in the majority of CRCs malignant clones canseed when the initial mass contains so few cells
then it is not clear how removal of an adenoma
during colonoscopy is so effective consideringthat adenomas contain >106 cells. The authors
seem to refer to a subset of cells within an adenoma (the so-called malignant clone), but theefficacy of colonoscopy indicates that evenwhen adenomas reach 108 cells (~1 cm3 in volume, the clinical detection limit) their removal
is highly effective and relapse (or metastases)
are not often detected 5–10 years after the procedure. As noted by the authors, a considerable number of patients with metastatic CRC

do not exhibit early systemic spread. Perhaps,
therefore, the fraction of ‘born to be bad’ CRCs
is in fact relatively small.
Up to two-thirds of distant metastases
and lymph node metastases originate fromindependent subclones within the primarycolorectal tumour9. It would, therefore, be very
useful to assess whether ‘born to be bad’ CRCs
metastasize through lymph nodes. Whether
the same patterns of early dissemination apply
to bowel tumours developing via the serrated
pathway, rather than by conventional tumorigenesis, is also unknown. In light of the above
points and the limited sample size of Hu et al.’s
study, further investigations are required todefine more accurately the fraction of CRCs
‘born to be bad’ as their identification could
indeed be clinically relevant.
How could ‘born to be bad’ CRCs bedetected early? One possibility might be combining invasive examinations such as sigmoidoscopy and colonoscopy with blood-based
tests such as liquid biopsies, which are aimed*e-mail: alberto.bardelli@unito.it
https://doi.org/10.1038/s41575-019-0200-4
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics,
2019. CA Cancer J. Clin 69, 7–34 (2019).
2.
Turajlic, S. & Swanton, C. Metastasis as anevolutionary process. Science 352, 169–175(2016).
3.
Jones, S. et al. Comparative lesion sequencing provides
insights into tumor evolution. Proc. Natl Acad. Sci. USA
105, 4283–4288 (2008).
4.
Hu, Z. et al. Quantitative evidence for early metastatic
seeding in colorectal cancer. Nat. Genet. 51,1113–1122 (2019).
5.
Ryser, M. D. et al. Spatial mutation patterns as markersof early colorectal tumor cell mobility. Proc. Natl Acad.
Sci. USA 115, 5774–5779 (2018).
6.
Consortium, A. P. G. AACR Project GENIE: Powering
Precision Medicine through an International Consortium.
Cancer Discov. 7, 818–831 CD-17-0151 (2017).
7.
Doubeni, C. A. et al. Effectiveness of screeningcolonoscopy in reducing the risk of death from rightand left colon cancer: a large community-based study.
Gut 67, 291–298 (2018).
8.
Lauby-Secretan, B. et al. The IARC Perspective on
Colorectal Cancer Screening. N. Engl. J. Med. 378,1734–1740 (2018).
9.
Naxerova, K. et al. Origins of lymphatic and distantmetastases in human colorectal cancer. Science 357,55–60 (2017).
10. Siravegna, G. et al. Integrating liquid biopsies into
the management of cancer. Nat. Rev. Clin. Oncol. 14,531–548 (2017).
1.

Acknowledgements
The authors thank Federica Di Nicolantonio for critically reading the manuscript. Research by A.B. is supported by theFondazione AIRC per la Ricerca sul Cancro under 5 per Mille
2018 (project 21091), AIRC investigator grant 2018 (project21923) and Fondazione Piemontese per la Ricerca sul Cancro
ONLUS 5 per mille 2014.

Competing interestsThe authors declare no competing interests.

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