2. Επιδημιολογικά Δεδομένα
• Ο καρκίνος του μαστού παραμένει ο πιο συχνός
καρκίνος στις γυναίκες και η δεύτερη ειδική για τη νόσο
αιτία θανάτου.
• Η συχνότερη αιτία θανάτου είναι οι επιπτώσεις από τις
απομακρυσμένες μεταστάσεις.
• Περίπου ένα 6% των ασθενών διαγιγνώσκονται με De
Novo μεταστατική νόσο και ένα 20–30% με πρώιμο
καρκίνο του μαστού θα υποτροπιάσουν σε
απομακρυσμένες θέσεις.
Henry NL et al, Abeloff’s Clin Oncol 1560-1603.e12 (2020)
O’Shaughnessy J. Oncologist. 2005;10 (Suppl 3):20–9
3. Μεταστατική Νόσος: Επιβίωση
•MDACC 1973-1982,
•1,544 MBC patients
•Treated w/ doxorubicin +
alkylating agent
•263 (16.6%) achieved complete
responses (CR)
•49 (3.1%) remained in CR for
more than 5 years..
Greenberg, P. A. et al, Journal of Clinical Oncology, 14(8), 2197–2205 1996
4. Μεταστατική Νόσος: Επιβίωση
•SEER 1998-2003
•15,438 with MBC:
-69% ER/PR+
•Risk of death decreased by 1-2% per year
•Improved survival with year diagnosed
•AA poorer survival.
S Dawood, et al, J Clin Oncol 26:4891-4898 2008
5. Φορτίο Μεταστατικής Νόσου: Επιβίωση
• 1.7% of 1,581 pts
remained alive/
complete remission >
10 yrs
• 619 pts treated with
anthracycline chemo
• Minimum f/u 4 yrs
G. N. Hortobagyi, et al, J Clin Oncol 1, No. 12 (December) 1983
7. Μεταστατική Νόσος: Καρκίνος του Μαστού
Hellman, S., & Weichselbaum, R. R., Journal of Clinical Oncology, Vol 13, No 1 (January), 1995: pp 8-10
•Halsted theory: breast cancer spread is orderly in a contiguous fashion from the
primary tumor through the lymphatics to the lymph nodes and then to distant sites.
•Systemic (Fisher) theory: clinically apparent cancer is a systemic disease. Early localized
breast cancer is an early manifestation which, if it is to metastasize, has already
metastasized. Lymph node involvement is not orderly contiguous extension, but rather a
marker of distant disease.
•Spectrum (Hellman) theory: cancer comprises a biologic spectrum extending from a
disease that remains localized to one that is systemic when first detectable but with
many intermediate states. Metastases are a function of both tumor size and tumor
progression.
• Supports that there are tumor states intermediate between purely localized disease and widely
metastatic
• Oligometastatic state: Tumors early in the chain of progression may have metastases limited in
number and location because the facility for metastatic growth has not been fully developed
11. De Novo Μεταστατική Νόσος του Μαστού
•Εμφάνιση ήδη από τη διάγνωση μεταστατικής νόσου ταυτόχρονα με
την πρωτοπαθή εστία.
•Αναδρομικές μελέτες υποστηρίζουν ευνοϊκότερη πρόγνωση για τις
ασθενείς με De Novo μεταστατική νόσου του μαστού.
•Οφείλεται μάλλον στη διαφορετική βιολογία της μεταστατικής νόσου
που αναπτύσσεται μετά από συστηματική θεραπεία.
12. Επιβίωση:De Novo vs. Υποτροπιάζουσα
Μεταστατική Νόσος του Μαστού
•MDACC 1992-2007
ꟷDeNovo 643 (18.2%)
ꟷRelapsed 2881 (81.8%)
•DeNovo:
ꟷOlder
ꟷHormone sensitive
•Median OS
ꟷDe Novo 39.2 months
ꟷRelapsed 27.2 months (p<.0001)
•Relapsed with DFI > 5 years similar mortality to
De novo
ꟷ(HR = 1.11, 95% CI 0.88–1.41, P = 0.38
Dawood et al., Annals of Oncology 21: 2169–2174, 2010
13. Επιβίωση:De Novo vs. Υποτροπιάζουσα
Μεταστατική Νόσος του Μαστού
•Cote d’Or Breast Cancer Registry
•2000-2011
•n=622 MBC
ꟷDeNovo ( primary): 282 (46%)
ꟷRelapsed ( secondary): 340 (54%)
•Median Survival:
ꟷDeNovo 24.5 Months
ꟷRelapsed 21.1 Months, (p = 0.10)
•Two year Survival:
ꟷDeNovo 50.8% [95% CI: 47.8–53.8%]
ꟷRelapsed 44% [95% CI: 41.8–47.2%]
•Poorer prognosis:
ꟷTNBC
ꟷOlder age
ꟷBrain or multiple first sites 1st metastases
Marshall et al, Breast J 21(2), 138-145 2017
14. Ολιγοϋποτροπιάζουσα Μεταστατική Νόσος
του Μαστού
•Πρόοδος σε μία ή λίγες μεταστατικές εντοπίσεις, ενώ οι υπόλοιπες
είναι σταθερές ή ανταποκρίνονται στη συστηματική θεραπεία.
ꟷ Η ασθενής ανέχεται καλώς τη θεραπεία
ꟷΗ κλασσική διαγνωστική προσέγγιση ανιχνεύει την
ασυμπτωματική νόσο.
•Θα μπορούσε η ριζική αντιμετώπιση των μεταστάσεων να επιμηκύνει
την ανταπόκριση στην τρέχουσα συστηματική θεραπεία; Θα μπορούσε
να βελτιώσει την PFS/OS;
15. Bazan et al, SABCS 2019
MBC Diagnosed 2013-2017 at the OSU-CCC (N=1,017)
16. Πρόγνωση Μεταστατικής Νόσου του Μαστού
Lobbezoo et al., Breast Cancer Res Treat (2013) 141:507–514
Bone only
Visceral only
Multiple Mets
18. Bed to Bench Approach
Από τις ασθενείς στον Φαινότυπο – Από τον Φαινότυπο στα Μόρια
Human tumor
samples
Micro-RNA
Predicted target
genes
Detection of important pathways
In vitro phenotypes
and targets
In vivo
experiments
Hallmarks of a cancer’s metastatic potential:
• Genotypic diversity,
• immortality,
• phenotypic plasticity at distant sites
19. Μεταστατική Αδράνεια και Εξέλιξη του
Καρκίνου
Peyvandi et al. J Cancer Metastasis Treat 2019;5:44
20. BCSCS και Μεταστατική Αδράνεια:
Διαφυγή από τη Διάγνωση και την Θεραπεία
Flynn et al. J Cancer Metastasis Treat 2019;5:43
21. Διακλαδισμένο Πρότυπο Γενετικής
Εξέλιξης κατά τη Μεταστατική Διαδικασία
P. Brastianos et al. Cancer Discov. 2015;5:1164–77.
• Matched samples of patients with
primary HER2+ breast cancer, brain
metastases, and normal tissue were
sequenced and evaluated for both
shared and unique mutations in
several key oncogenes and tumor
suppressors.
• Although most patients had a set of
shared mutations, both the primary
tumor and the brain metastases
harbored unique mutations,
implicating that both primary and
metastatic lesions continued to
evolve separately once metastasis
had occurred
22. Οι Ολιγομεταστάσεις Προκαλούν Διάχυτη
Μεταστατική Νόσο μέσω Μοριακών Μεταβολών
YA. Lussier et al. PLoS One; 6:e28650, 2011
32 pts
No recurrence, Slow
Oligometastases
16 pts
Rapid Polymetastases
Criteria:
1-5 metastases Resectable
>16 mo f-u
63 pts
followed
Patients segregated by the
rate of metastases recurrence
New dimension in oligometastases definition –
TIME, not just numbers
Slow ≤ 0.6 mets/year
Rapid ≥ 3.6 mets/year
23. Η Βιολογία της Ολιγομετάστασης
YA. Lussier et al. PLoS One; 6:e28650, 2011
24. Το14q32-encoded microRNAs Προάγει έναν Ολιγομεταστατικό
AIM Φαινότυπο (Adhesion/Invasion/Migration
A.Uppal et al, Oncotarget;6:3540–52. 2015
Over-expression of 14q32-encoded microRNAs
(miR-127-5q, miR-544a and miR-655-3p) is
associated with improved recurrence free
survival in patients undergoing surgical resection
of lung metastases
AIM group: regulation of cell
adhesion, cell-extracellular matrix
interaction, and cell motility
14q32 microRNA dependent regulation
of an oligometastatic phenotype
through co- repression of target genes
25. Το14q32-encoded microRNAs Προάγει έναν Ολιγομεταστατικό
AIM Φαινότυπο (Adhesion/Invasion/Migration)
A.Uppal et al, Oncotarget;6:3540–52. 2015
26. Καρκίνος Παχέος Εντέρου -
Ολιγομετάσταση
Pitroda SP, et al. Nature Comm, 9(1):1793; 2018
• 134 patients with resected liver
oligometastasis from colorectal
cancers
• Patients were uniformly treated
with pre-op chemo, definitive
treatment of primary cancer and
partial hepatectomy for resection of
liver metastases
• 61% with only 1 met; 22% with 2
met. and 17% with 3 or more met
• Methods
• Whole genome RNA sequencing of
95 samples
• Microsatellite instability analysis in
89 samples
113-gene signature validated in independent MSKCC dataset
27. Integrated mRNA-miRNA Analysis
Pitroda SP, et al. Nature Comm, 9(1):1793; 2018
Analysis of parallel miRNA
and mRNA networks in 93
patient samples independent
of clinical or survival data
28. Integration of Intrinsic Molecular
Subtypes and Clinical Risk Stratification
Pitroda SP, et al. Nature Comm, 9(1):1793; 2018
113-gene signature validated in
independent MSKCC dataset
29. Integration of Intrinsic Molecular
Subtypes and Clinical Risk Stratification
Pitroda SP, et al. Nature Comm, 9(1):1793; 2018
30. Συμπεράσματα
Pitroda SP, et al. Nature Comm, 9(1):1793; 2018
• Οι μοριακοί υπότυποι συμπληρώνουν την κλινική ταξινόμηση
του κινδύνου υποτροπής
• Η γονιδιακή έκφραση δίνει σημαντικές θεραπευτικές
πληροφορίες και κατευθύνσεις
• Ο «όλιγο» φαινότυπος είναι μια σύμπλοκη συσχέτιση μεταξύ
όγκου και ξενιστή
• Μπορεί να καθορίζουμε «όλιγο» και «πόλυ» κατάσταση,
όμως στην κλινική πράξη παρατηρείται ένα φάσμα μεταξύ
των δύο
• Η μοριακή ανάλυση πρέπει να διενεργείται με σκοπό την
κατηγοριοποίηση της μεταστατικής κατάστασης
31. Επιγενετική Ρύθμιση της Μετάστασης- Κατασταλτικά
miRNAs και Επίδραση στη Μετάσταση
G. Oshima, et al. Cancer Res; 79(3) February 1, 2019
• Overexpression of DNA methylation–dependent 14q32
miRNAs in clinical metastases is associated with improved
survival
• Pharmacologic DNA demethylation by 5-Aza-dC induces 14q32 miRNA
expression and restricts liver metastasis
• Reactivation of 14q32 miRNAs is sufficient to restrict liver metastasis
• Identification of DNA methylation–dependent regulatory elements
controlling 14q32 miRNA expression
• MEG3-DMR regulatory element controls transcription of 14q32
miRNAs through DNA methylation-dependent CTCF binding
• Methylation status of MEG3-DMR promoter in different cancer cells is
associated with inducible or constitutive expression of 14q32 miRNAs
and AIM phenotype of tumor clones
32. Βιολογία της Ολιγομετάστασης:
Έχει Ρόλο ο Ξενιστής;
Hemminki K, et al. Oncotarget 2016; 7:22140 49
• Metastatic spreading is associated with some
polymorphisms
• Case-control study of patient with carcinoma of
unknown primary (by definition, systemic bulky
metastatic disease) –genome-wide association study
• At least, 8 polymorphisms are associated with
CUP diagnosis (p<10-6)
• rs2660852 located closed to LTAH4H gene
(leukotriene A4 hydrolase)
• rs477145 of TIAM1 gene (T-cell lymphoma
invasion and metastases)
• s2835931 of KCNJ6 gene …
• Genes involved in cellular motility, interaction cell
control, cell adhesion …
33. «Αληθής» και «Ψευδής» Ολιγομεταστατική
Νόσος
• 1.“True” oligometastatic disease as initially defined, with
relative steady-state and slowly growing disease. In this case,
local control of oligometastases makes sense
• 2.“False” oligometastatic disease. In this case the occult
systemic spreading is ongoing, but a limited number of
metastatic sites are detectable. In this case, systemic treatment
is needed
35. Τοπική Θεραπεία Στοχεύουσα την Πρωτοπαθή
Εστία (Μαστός) ή τη Μετάσταση: Σκεπτικό
• Λιγότερη νόσος: περισσότερο επιθυμητή από τον θεράποντα και την
ασθενή
• Πρώιμη τοπική θεραπεία:
• Καθυστέρηση συμπτωμάτων, σκελετικών συμβαμάτων
• Καταστροφή των ανθεκτικών στη συστηματική θεραπεία κυττάρων
• Καθυστέρηση έναρξης συστηματικής ή αλλαγής συστηματικής θεραπείας
• Ίαση της μεταστατικής νόσου;
• Δραστική και ασφαλής λόγω εξελιγμένων μεθόδων και τεχνικών στη
Χειρουργική και την Ακτινοθεραπεία
• SABR
38. Στερεοτακτική Ακτινοθεραπεία (SABR)
• Υψηλή ακρίβεια
• Μικρού μεγέθους όγκοι στόχοι
• Μικρός αριθμός συνεδριών (1-8)
• Υψηλή δόση ανά συνεδρία
• Διαφορετική ραδιοβιολογική επίδραση σε
σύγκριση με την κλασσική κλασματοποίηση
39. (SABR) Πλεονεκτήματα
• Μη επεμβατική θεραπεία
• Υψηλός τοπικός έλεγχος (70–100%)
• Μικρή τοξικότητα και θνητότητα
• Cost-effective
• Μπορεί να υπερκεράσει την
ακτινοαντοχή
40. SABR - Κλινικές Μελέτες
Author/year Disease Design Definition n patients Intervention Outcome Results
Palma D. 2019 Mixed Prospective, randomized
phase II
≤ 5 lesions 99 SABR vs palliative
standard of care
Median OS 28 mo control vs 41 mo SABR
Trovo M. 2018 Breast Prospective, single arm,
phase II
≤ 5 sites 54 SBRT 30–45 Gy or IMRT
60 Gy
Primary: PFS
Secondary: OS
1 year 75%
2 years 53% 2 years 95%
Scorsetti M. 2018 Mixed Prospective, single arm,
phase II
≤ 3 liver sites 61 SBRT to liver metastases Primary: LC
Secondary: OS
1 year 94%
3 years 78%
5 years 78% mOS 27.6mo
Milano MT. 2008 Mixed Prospective, single arm ≤ 5 sites 121 SBRT 5 Gy OS
PFS
LC
DC
2-year OS 50%
26%
67%
34%
Salama 2012 Mixed Prospective, single arm ≤ 5 metastases 61 SBRT OS 1 year 81.5%
2 years 56.7%
Onal C. 2018 Breast Retrospective ≤ 5 metastases 22 SBRT Local control rate
OS
PFS
2 years 88%
2 years 57%
2 years 8%
Andratschke N. 2018 Mixed Retrospective ≤ 4 liver metastases 474 SBRT OS
1-year control rate
2-year control rate
Median 24 mo
77%
6%
Bhattacharya I. 2015 Mixed Retrospective ≤ 3 metastases 76 SBRT 2-year OS
2-year PFS
63.2%
26.2%
Mahadevan A. 2018 Mixed Retrospective Liver metastases 427 SBRT OS Median 22 months
Breast 21 months
Loi M. 2018 Mixed Retrospective ≤ 3 lymph node
metastases
91 SBRT Locoregional RFS
Distant Metastasis Free
Survival
4 years 79%
4 years 44%
Fumagalli I. 2012 Mixed Retrospective ≤ 5 sites 90 SBRT LC
OS
DFS
1 year 84.5%
2 years 66.1% 2 years OS 70%
mDFS 6.7 mo
Rades D. 2018 Breast Retrospective 1–4 vertebrae 159 Radiotherapy LC
OS
2 years 87%
2 years 67%
41. SBRT for Oligometastases
University of Rochester Experience
Milano et al. Int J Radiation Oncol Biol Phys, Vol. 83, No. 3, pp. 878e886, 2012
• Prospectively followed 121 patients
with various oligometastatic cancers
(39 breast cancers)
• stereotactic body radiotherapy (SBRT).
• OM: defined as ≤ 5 lesions in ≤ 3
organs.
• For the breast cancer cohort,
• 2-, 4-, and 6-year OS rate of
74%, 54%, and 47%
• 2-, 4-, and 6-year FFDM rate of
52%, 43%, and 36%
• 31, 22, and 14 patients at risk at
2, 4, and 6 years,
Breast Cancer
42. HSRT for Oligometastatic Breast Cancer
University of Rochester Experience
M.T. Milano et al. Radiotherapy and Oncology 131 (2019) 45–51
• 48 pts
• 1-5 extracranial BC oligometastases
• SBRT to all radiographically apparent sites of disease
• BO oligometastases
• 5y OS: 83%
• 10y OS: 75%
• all other pts
• 5y OS: 31%
• 10y OS: 17%
• Freedom From Widespread Metastases (FFWM):
• BO oligometastes
• number of organs involved
• number of oligometastatic lesions
• GTV of metastases>25cc
• BO oligometastes pts: younger, synchronous OM, HR
positive disease
BO oligometastases
43. Radiotherapy for Oligometastatic BC
M. Trovo et al. Radiotherapy and Oncology 2018;126:177–80
• 54 Patients with 92 metastatic lesions
• Inclusion criteria:
• oligometastatic BC with ≤ 5 metastatic
sites, FDG-PET/CT staging, no brain
metastases, primary tumor controlled
• Radiotherapy:
• SBRT 30–45 Gy in 3 fractions, IMRT 60
Gy in 25 fractions
• Follow-up of 30 months 1- and 2-year
• PFS was 75% and 53%, respectively
• Two-year LC and OS were 97% and 95%,
respectively
• Grade 2 toxicity pain and fatigue in 2
cases
44. SBRT for Oligometastatic Breast Cancer
Liver Metastasis (BCLM)
C. Onal et al. The Breast 42 (2018) 150e156
• 22 patients with oligometastasis at the time of
liver metastasis (LM) or who became
oligometastatic (≥5 metastases) after systemic
treatment (29 liver metastatic lesions)
• SBRT:
• 54 Gy delivered in 3 fractions
• Median follow-up16.0 months:
• 18 patients (82%) had disease recurrence,
median of 7.4 months after completion of liver
SBRT.
• 1- and 2-year OS rates were 85% and 57%
• 1- and 2- year PFS rates were 38% and 8%
• 1- and 2-year LC rates were 100% and 88%
• Toxicity:
• one patient rib fracture 6months after
completion of treatment
• one patient duodenal ulcer
Conclusion: Liver SBRT is a conservative approach with
excellent LC and limited toxicities
45. SABR for Oligometastases? COMET Study
Palma, D., Lancet S0140-6736(19)30278-8 2019
• Phase II, 2-sided P of 0.2
• 99 patients ≤ 5 distant
lesions
• The majority of cancers
were breast, lung, and
prostate
• Majority had 1-3 lesion
• Grade 5 toxicity for SABR
higher than expected
46. NRG-BR002: A Phase IIR/III Trial of Standard of Care Therapy with
or without Stereotactic Body Radiotherapy (SBRT) and/or Surgical
Ablation for Newly Oligometastatic Breast Cancer
PI: Steve Chmura
ClinicalTrials.gov NCT02364557
• Phase IIr:
-Hypothesis: ablative local therapy all visible
lesions with systemic therapy gives a signal
for meaningful improvement in the PFS to
warrant continuation to Phase III trial
-Power to improve PFS from 10.5 to 19.5
months
-Current enrollment 67/125
• Phase III:
-Hypothesis: Multi-modality tx of
oligometastases improves 5-yr OS
-Additional 246 patients
-Power to improve overall survival 28% to
42.5%
47. STEREO SEIN: Essai de supériorité de phase III de radiothérapie
stéréotaxique pour les patientes atteintes de cancer du sein en
première ligne métastatique.
PI: Dr Sofia RIVERA
NUMÉRO DE L'ÉTUDE: IGR 1957
•On going phase III trial
•De novo OMBC, HR positive ≤5 metastatic lesions
•Standard arm
•Standard of care systemic treatment
•Experimental arm
•Standard of care systemic treatment + SABR or Surgery
48. Μελλοντικές Κατευθύνσεις
Ταυτοποίηση των βιολογικών παραγόντων που σχετίζονται με το ολιγομεταστατικό
πρότυπο
Θεραπευτικές προσεγγίσεις έναντι των συγκεκριμένων βιολογικών παραγόντων
Λεπτομερέστερος ορισμός της ολιγομεταστατικής νόσου για κάθε κλινική
κατάσταση
Διενέργεια φάσης ΙΙΙ μελετών
Κατάλληλος συνδυασμός τοπικών και συστηματικών θεραπειών
49. Συμπερασματικά …
Πολλαπλοί ορισμοί σχετιζόμενοι με τον τύπο του καρκίνου και τις διαγνωστικές μεθόδους.
Περιλαμβάνει δύο κατά βάση κατηγορίες: « αληθής » με ήπια όλιγο- μεταστατική νόσο και «
ψευδής » εξελισσόμενη συστηματική νόσος
Υπάρχουν μοριακές υπογραφές σχετιζόμενες με την ολιγομετάσταση στον καρκίνο του
παχέος εντέρου και του νεφρού
Ο ρόλος του ξενιστή χρήζει έρευνας
Προς το παρόν, δεν υπάρχουν επαρκή δεδομένα για τη χορήγηση τοπικών θεραπειών στην
ολιγομετάσταση
Αντιθέτως υπάρχει τεχνολογική εξέλιξη που επιτρέπει την χορήγηση τοπικών θεραπειών με
ασφάλεια (SBRT, radio ablation, cryotherapy, mini invasive surgery…)
Απαιτούνται μεγάλες καλά σχεδιασμένες φάσης ΙΙΙ μελέτες
Απαιτούνται μοριακές υπογραφές δηλωτικές της ολιγομετάσταση και για τους υπόλοιπους
καρκίνους
Editor's Notes
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer.
In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-20-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster.
DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-
DMR), which acts as a cis-regulatory element for 14q32miRNA expression. 5-Aza-dC activated demethylation of the MEG3- DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells.
Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC–induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver
metastasis and correlated with improved clinical outcomes in patients with metastatic cancer.
These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs.
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer.
In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-20-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster.
DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-
DMR), which acts as a cis-regulatory element for 14q32miRNA expression. 5-Aza-dC activated demethylation of the MEG3- DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells.
Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC–induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver
metastasis and correlated with improved clinical outcomes in patients with metastatic cancer.
These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs.
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer.
In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-20-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster.
DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-
DMR), which acts as a cis-regulatory element for 14q32miRNA expression. 5-Aza-dC activated demethylation of the MEG3- DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells.
Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC–induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver
metastasis and correlated with improved clinical outcomes in patients with metastatic cancer.
These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs.
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer.
In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-20-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster.
DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-
DMR), which acts as a cis-regulatory element for 14q32miRNA expression. 5-Aza-dC activated demethylation of the MEG3- DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells.
Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC–induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver
metastasis and correlated with improved clinical outcomes in patients with metastatic cancer.
These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs.
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer.
In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-20-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster.
DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-
DMR), which acts as a cis-regulatory element for 14q32miRNA expression. 5-Aza-dC activated demethylation of the MEG3- DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells.
Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC–induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver
metastasis and correlated with improved clinical outcomes in patients with metastatic cancer.
These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs.
Expression of 14q32-encoded miRNAs is a favorable prognostic factor in patients with metastatic cancer.
In this study, we used genomic inhibition of DNA methylation through disruption of DNA methyltransferases DNMT1 and DNMT3B and pharmacologic inhibition with 5-Aza-20-deoxycytidine (5-Aza-dC, decitabine) to demonstrate that DNA methylation predominantly regulates expression of metastasis-suppressive miRNAs in the 14q32 cluster.
DNA demethylation facilitated CCCTC-binding factor (CTCF) recruitment to the maternally expressed gene 3 differentially methylated region (MEG3-
DMR), which acts as a cis-regulatory element for 14q32miRNA expression. 5-Aza-dC activated demethylation of the MEG3- DMR and expression of 14q32 miRNAs, which suppressed adhesion, invasion, and migration (AIM) properties of metastatic tumor cells.
Cancer cells with MEG3-DMR hypomethylation exhibited constitutive expression of 14q32 miRNAs and resistance to 5-Aza-dC–induced suppression of AIM. Expression of methylation-dependent 14q32 miRNAs suppressed metastatic colonization in preclinical models of lung and liver
metastasis and correlated with improved clinical outcomes in patients with metastatic cancer.
These findings implicate epigenetic modification via DNA methylation in the regulation of metastatic propensity through miRNA networks and identify a previously unrecognized action of decitabine on the activation of metastasis-suppressive miRNAs.