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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