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Klaus Pantel
Institut für Tumorbiologie
Tumor cell dissemination, cancer dormancy,
circulating tumor cells and metastasis
Tumor cell dissemination
and cancer dormancy
Cancer cells disseminate early into the bone
marrow and pose a risk for subsequent relapse
Primary tumor
Local relapse
Blood
CTCs
(Braun/Pantel et al., NEJM, 2005; Köllermann/Pantel et al., J
Clin Oncol., 2008)
VCAM1, Jagged-1 and tumor-induced osteoclast
miRNAs as regulators of progression from DTCs
to bone metastases (Lu/Pantel/Kang et al Cancer Cell
Distant tissue
(e.g. bone marrow)
Recirculation
DTCs
2011; Ell/Pantel/Kang et al, Cancer Cell 2013; BednarzKnoll, Kang Pantel et al, Clin Chem 2016)
Metabolic adaptation of DTCs is important for
survival (LeBleu, Pantel, Kalluri et al, Nature Cell Biol.
2014)
DTC
Tumor cell
dormancy
Tumormass
dormancy
RAI2 as new metastasis-suppressor (Werner,
Wikman, Wilmanns, Pantel et al, Cancer Discovery 2015)
Micrometastasis
DTCs persist in the bone marrow through sustained
activation of the unfolded protein response
Escape
(Bartkowiak, Pantel et al., Cancer Res. 2015)
Exosome-mediated homing of metastatic cells to
specific distant sites (Hoshino, Pantel, Bissell,
Peinado, Lyden et al., Nature, 2015)
NATURE REVIEWS CLINICAL ONCOLOGY
Metastasis
VOLUME 6 JUNE 2009
339
DTC in bone marrow of cancer patients
Breast Cancer: 199/552 (36%)
Bone
marrow
(Braun, Pantel et al. NEJM, 2000 & 2005)
Prostate Cancer: 86/193 (44.6%)
(Koellermann/Pantel et al. JCO 2008)
Ficoll
gradient
correlates
with
Nonmalignant disease: 2/191 (1%)
• DTC detection
metastatic AND locoregional relapse
• Most DTC are Ki67- and
MNChave CD44+/CD24- stem cell phenotype
Bone marrow
aspirates
• DTCs
can occupy the hematopoietic stem cell niches
taken from the upper iliac
crest
Immunocytochemistry:
Cytokeratin staining
with mAB A45-B/B3
2 x 106 MNC
per patient
BM is a homing organ and putative reservoir
for DTC derived from various primary sites
Tumor type
Detection rate (%)
Breast Cancer
20-40
Prostate cancer*
20-30
Lung cancer (NSCLC)
40-60
Gastric cancer
35-60
Esophageal cancer
30-40
Colorectal cancer
20-30
Pancreatic cancer
10-20
Head and neck cancer
20-30
Is hematogeneous dissemination of
cancer cells an early event in tumor
progression?
Detection of DTC in bone marrow of patients
with ductal carcinoma in situ (DCIS)
In 7/30 (23.3%) patients with pure DCIS and in 5/12 (41.7%)
patients with DCIS plus microinvasion of the basement
membrane DTC were detected (Sänger/Effenberger/Pantel et al., IJC 2011)
BUT: Distant metastases are rare (3 %) -> Dormancy
Cancer Dormancy: Research questions
• Do all cancer patients have dormant tumor cells?
• Can host factors induce or break dormancy? Stress? Inflammation?
• Are there preferred reservoirs of dormant cells (e.g., bone marrow) ?
• Does the immune system play a role in dormancy?
• What is the effect of current therapies on dormant cells or
dormancy?
• What signaling pathways or events reactivate dormant cells?
• Do dormant cells have properties of cancer stem cells?
• How does genetic background affect dormancy?
Kang & Pantel, Cancer Cell 2013
Immune escape mechanisms of CTCs in the peripheral blood
Mohme, Riethdorf & Pantel, Nature Rev Clin Oncol 2016
Detection of CTC in the peripheral blood
Advantages over DTC detection:
• Less invasive than BM sampling
• Pool of DTC from multiple distant sites
2010
Aims of Liquid Biopsy
• Screening & early detection of cancer
• Estimation of the risk for metastatic relapse or
metastatic progression (prognostic information)
• Stratification & real-time monitoring of therapies
• Identification of therapeutic targets and resistance
mechanisms (biological therapies)
• Understanding the biology of metastatic development
CTC as Liquid Biopsy
for metastatic cells
Metastasis evolve many years
after primary tumor resection
and can harbor unique genomic
alterations.
Biopsy of metastases is an
invasive and sometimes
dangerous procedure.
Intra-patient heterogeneity of
metastases at different sites
CTC/ctDNA might reveal
representative information
on metastatic cells located at
different sites
Alix-Panabières & Pantel, Clin
Chem, 2013; Pantel & AlixPanabieres, Cancer Res. 2013