Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 3/2012

01-03-2012 | Research Paper

Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas

Authors: Vanisri Raviraj, Hui Zhang, Hsin-ya Chien, Louise Cole, Erik W. Thompson, Lilian Soon

Published in: Clinical & Experimental Metastasis | Issue 3/2012

Login to get access

Abstract

Mortality in breast cancer is linked to metastasis and recurrence yet there is no acceptable biological model for cancer relapse. We hypothesise that there might exist primary tumour cells capable of escaping surgery by migration and resisting radiotherapy and chemotherapy to cause cancer recurrence. We investigated this possibility in invasive ductal carcinoma (IDC) tissue and observed the presence of solitary primary tumour cells (SPCs) in the dense collagen stroma that encapsulates intratumoural cells (ICs). In IDC tissue sections, collagen was detected with either Masson’s Trichrome or by second harmonics imaging. Cytokeratin-19 (CK-19) and vimentin (VIM) antibodies were, respectively, used to identify epithelial-derived tumour cells and to indicate epithelial to mesenchymal transition (EMT). Confocal/multiphoton microscopy showed that ICs from acini were mainly CK-19+ve and were encapsulated by dense stromal collagen. Within the stroma, SPCs were detected by their staining for both CK-19 and VIM (confirming EMT). ICs and SPCs were subsequently isolated by laser capture microdissection followed by multiplex tandem-PCR studies. SPCs were found to be enriched for pro-migratory and anti-proliferative genes relative to ICs. In vitro experiments using collagen matrices at 20 mg/cm3, similar in density to tumour matrices, demonstrated that SPC-like cells were highly migratory but dormant, phenotypes that recapitulated the genotypes of SPCs in clinical tissue. These data suggest that SPCs located at the breast cancer perimeter are invasive and dormant such that they may exceed surgical margins and resist local and adjuvant therapies. This study has important connotations for a role of SPCs in local recurrence.
Appendix
Available only for authorised users
Literature
1.
Wyckoff JB et al (2000) A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res 60(9):2504–2511PubMed
2.
Pantel K et al (2003) Detection and clinical implications of early systemic tumor cell dissemination in breast cancer. Clin Cancer Res 9(17):6326–6334PubMed
3.
Braun S et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802PubMedCrossRef
4.
5.
Li CI, Daling JR (2007) Changes in breast cancer incidence rates in the United States by histologic subtype and race/ethnicity, 1995 to 2004. Cancer Epidemiol Biomarkers Prev 16(12):2773–2780PubMedCrossRef
6.
Sinha PS, Bendall S, Bates T (2000) Does routine grading of invasive lobular cancer of the breast have the same prognostic significance as for ductal cancers? Eur J Surg Oncol 26(8):733–737PubMedCrossRef
7.
Wyckoff J et al (2004) A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 64(19):7022–7029PubMedCrossRef
8.
Wyckoff JB et al (2007) Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 67(6):2649–2656PubMedCrossRef
9.
Robinson BD et al (2009) Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res 15(7):2433–2441PubMedCrossRef
10.
Gertler F, Condeelis J (2011) Metastasis: tumor cells becoming MENAcing. Trends Cell Biol 21(2):81–90PubMedCrossRef
11.
Meng S et al (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162PubMedCrossRef
12.
Aguirre-Ghiso JA, Ossowski L, Rosenbaum SK (2004) Green fluorescent protein tagging of extracellular signal-regulated kinase and p38 pathways reveals novel dynamics of pathway activation during primary and metastatic growth. Cancer Res 64(20):7336–7345PubMedCrossRef
13.
Indraccolo S et al (2006) Interruption of tumor dormancy by a transient angiogenic burst within the tumor microenvironment. Proc Natl Acad Sci USA 103(11):4216–4221PubMedCrossRef
14.
Naumov GN et al (2006) A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst 98(5):316–325PubMedCrossRef
15.
Woodcock-Mitchell J et al (1982) Immunolocalization of keratin polypeptides in human epidermis using monoclonal antibodies. J Cell Biol 95(2 Pt 1):580–588PubMedCrossRef
16.
Folpe AL, Cooper K (2007) Best practices in diagnostic immunohistochemistry: pleomorphic cutaneous spindle cell tumors. Arch Pathol Lab Med 131(10):1517–1524PubMed
17.
Stanley KK, Szewczuk E (2005) Multiplexed tandem PCR: gene profiling from small amounts of RNA using SYBR Green detection. Nucleic Acids Res 33(20):e180PubMedCrossRef
18.
Whitehead RH et al (1983) A new human breast carcinoma cell line (PMC42) with stem cell characteristics. I. Morphologic characterization. J Natl Cancer Inst 70(4):649–661PubMed
19.
Sakaue-Sawano A et al (2008) Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132(3):487–498PubMedCrossRef
20.
Sapino A, Frigerio A, Peterse JL, Arisio R, Coluccia C, Bussolati G (2000) Mammographically detected in situ lobular carcinomas of the breast. Virchows Arch 436(5):421–430PubMedCrossRef
21.
Lee JM et al (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973–981PubMedCrossRef
22.
Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428PubMedCrossRef
23.
Mendez MG, Kojima S, Goldman RD (2010) Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J 24(6):1838–1851PubMedCrossRef
24.
Yasui W et al (2004) Search for new biomarkers of gastric cancer through serial analysis of gene expression and its clinical implications. Cancer Sci 95(5):385–392PubMedCrossRef
25.
Fonsato V et al (2006) Expression of Pax2 in human renal tumor-derived endothelial cells sustains apoptosis resistance and angiogenesis. Am J Pathol 168(2):706–713PubMedCrossRef
26.
Chen Q, DeGraff DJ, Sikes RA (2010) The developmental expression profile of PAX2 in the murine prostate. Prostate 70(6):654–665PubMed
27.
Chu CY et al (2008) Connective tissue growth factor (CTGF) and cancer progression. J Biomed Sci 15(6):675–685PubMedCrossRef
28.
Barsky SH et al (1997) ‘Revertant’ DCIS in human axillary breast carcinoma metastases. J Pathol 183(2):188–194PubMedCrossRef
29.
Lipponen P et al (1994) Tumour vascularity and basement membrane structure in breast cancer as related to tumour histology and prognosis. J Cancer Res Clin Oncol 120(11):645–650PubMedCrossRef
30.
Pierga JY et al (2004) Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 10(4):1392–1400PubMedCrossRef
31.
Muller V et al (2005) Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 11(10):3678–3685PubMedCrossRef
32.
Klein CA (2003) The systemic progression of human cancer: a focus on the individual disseminated cancer cell: the unit of selection. Adv Cancer Res 89:35–67PubMedCrossRef
33.
Husemann Y et al (2008) Systemic spread is an early step in breast cancer. Cancer Cell 13(1):58–68PubMedCrossRef
34.
Thompson EW, Newgreen DF, Tarin D (2005) Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 65(14):5991–5995 discussion 5PubMedCrossRef
35.
Sorlie T et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874PubMedCrossRef
36.
Hollier BG, Evans K, Mani SA (2009) The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 14(1):29–43PubMedCrossRef
37.
Mani SA et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715PubMedCrossRef
38.
Li C, Lee CJ, Simeone DM (2009) Identification of human pancreatic cancer stem cells. Methods Mol Biol 568:161–173PubMedCrossRef
39.
Creighton CJ, Chang JC, Rosen JM (2010) Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J Mammary Gland Biol Neoplasia 15(2):253–260PubMedCrossRef
40.
Armstrong AJ et al (2011) Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res 9(8):997–1007PubMedCrossRef
41.
Blick T et al (2010) Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia 15(2):235–252PubMedCrossRef
42.
Trimboli AJ et al (2008) Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res 68(3):937–945PubMedCrossRef
43.
Yoder BJ et al (2005) The expression of fascin, an actin-bundling motility protein, correlates with hormone receptor-negative breast cancer and a more aggressive clinical course. Clin Cancer Res 11(1):186–192PubMed
44.
Cooper D, Schermer A, Sun TT (1985) Classification of human epithelia and their neoplasms using monoclonal antibodies to keratins: strategies, applications, and limitations. Lab Invest 52(3):243–256PubMed
45.
Datta YH et al (1994) Sensitive detection of occult breast cancer by the reverse-transcriptase polymerase chain reaction. J Clin Oncol 12(3):475–482PubMed
46.
Braun S et al (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342(8):525–533PubMedCrossRef
47.
Kallergi G et al (2007) Phosphorylation of FAK, PI-3K, and impaired actin organization in CK-positive micrometastatic breast cancer cells. Mol Med 13(1–2):79–88PubMed
48.
Becker S et al (2009) Evaluation of a RT-PCR based routine screening tool for the detection of disseminated epithelial cells in the bone marrow of breast cancer patients. Breast Cancer Res Treat 117(2):227–233PubMedCrossRef
49.
Moody SE et al (2005) The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8(3):197–209PubMedCrossRef
50.
Lang SH et al (2002) Enhanced expression of vimentin in motile prostate cell lines and in poorly differentiated and metastatic prostate carcinoma. Prostate 52(4):253–263PubMedCrossRef
51.
52.
Sorlie T et al (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423PubMedCrossRef
53.
Prat A et al (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12(5):R68PubMedCrossRef
54.
Wang W et al (2004) Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 64(23):8585–8594PubMedCrossRef
55.
Barr FG (1997) Chromosomal translocations involving paired box transcription factors in human cancer. Int J Biochem Cell Biol 29(12):1449–1461PubMedCrossRef
56.
Muratovska A et al (2003) Paired-box genes are frequently expressed in cancer and often required for cancer cell survival. Oncogene 22(39):7989–7997PubMedCrossRef
57.
Gnarra JR, Dressler GR (1995) Expression of Pax-2 in human renal cell carcinoma and growth inhibition by antisense oligonucleotides. Cancer Res 55(18):4092–4098PubMed
58.
Silberstein GB, Dressler GR, Van Horn K (2002) Expression of the PAX2 oncogene in human breast cancer and its role in progesterone-dependent mammary growth. Oncogene 21(7):1009–1016PubMedCrossRef
59.
Buttiglieri S et al (2004) Role of Pax2 in apoptosis resistance and proinvasive phenotype of Kaposi’s sarcoma cells. J Biol Chem 279(6):4136–4143PubMedCrossRef
60.
Roy-Burman P et al (2004) Genetically defined mouse models that mimic natural aspects of human prostate cancer development. Endocr Relat Cancer 11(2):225–254PubMedCrossRef
61.
Peehl DM (2005) Primary cell cultures as models of prostate cancer development. Endocr Relat Cancer 12(1):19–47PubMedCrossRef
62.
Xiaogang R et al (2008) Study of tumor molecular diagnosis model based on artificial neural network with gene expression profile. Evolutionary Computation, 2008 CEC 2008 (IEEE World Congress on Computational Intelligence) IEEE Congress on 1–6 June 2008, p 1051–1056
63.
Wong AS, Gumbiner BM (2003) Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol 161(6):1191–1203PubMedCrossRef
64.
Larue L, Bellacosa A (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24(50):7443–7454PubMedCrossRef
65.
Klymkowsky MW, Savagner P (2009) Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol 174(5):1588–1593PubMedCrossRef
66.
Jechlinger M et al (2003) Expression profiling of epithelial plasticity in tumor progression. Oncogene 22(46):7155–7169PubMedCrossRef
67.
Barbolina MV et al (2009) Downregulation of connective tissue growth factor by three-dimensional matrix enhances ovarian carcinoma cell invasion. Int J Cancer 125(4):816–825PubMedCrossRef
68.
Brigstock DR (1999) The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 20(2):189–206PubMedCrossRef
69.
70.
Zheng HC et al (2008) Arp2/3 overexpression contributed to pathogenesis, growth and invasion of gastric carcinoma. Anticancer Res 28(4B):2225–2232PubMed
71.
Rohatgi R, Ho HY, Kirschner MW (2000) Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4,5-bisphosphate. J Cell Biol 150(6):1299–1310PubMedCrossRef
72.
Mizutani K et al (2002) Essential role of neural Wiskott–Aldrich syndrome protein in podosome formation and degradation of extracellular matrix in src-transformed fibroblasts. Cancer Res 62(3):669–674PubMed
73.
Yamaguchi H et al (2005) Molecular mechanisms of invadopodium formation: the role of the N-WASP-Arp2/3 complex pathway and cofilin. J Cell Biol 168(3):441–452PubMedCrossRef
74.
Innocenti M et al (2004) Abi1 is essential for the formation and activation of a WAVE2 signalling complex. Nat Cell Biol 6(4):319–327PubMedCrossRef
75.
Kurisu S et al (2005) Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells. Oncogene 24(8):1309–1319PubMedCrossRef
76.
Rodriguez-Pinilla SM et al (2006) Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res 12(5):1533–1539PubMedCrossRef
77.
78.
Leung T et al (1995) A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem 270(49):29051–29054PubMedCrossRef
79.
Bhadriraju K et al (2007) Activation of ROCK by RhoA is regulated by cell adhesion, shape, and cytoskeletal tension. Exp Cell Res 313(16):3616–3623PubMedCrossRef
80.
Riento K, Ridley AJ (2003) Rocks: multifunctional kinases in cell behaviour. Natl Rev Mol Cell Biol 4(6):446–456CrossRef
81.
Bourguignon LY et al (1999) Rho-kinase (ROK) promotes CD44v(3,8-10)-ankyrin interaction and tumor cell migration in metastatic breast cancer cells. Cell Motil Cytoskelet 43(4):269–287CrossRef
82.
Yoshioka K, Nakamori S, Itoh K (1999) Overexpression of small GTP-binding protein RhoA promotes invasion of tumor cells. Cancer Res 59(8):2004–2010PubMed
83.
Hunter T, Pines J (1994) Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell 79(4):573–582PubMedCrossRef
84.
85.
Zhang H, Xiong Y, Beach D (1993) Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes. Mol Biol Cell 4(9):897–906PubMed
86.
Polyak K et al (1994) Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78(1):59–66PubMedCrossRef
87.
Han SH et al (2003) VDUP1 upregulated by TGF-beta1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene 22(26):4035–4046PubMedCrossRef
88.
89.
Christov K et al (2003) Cell proliferation, apoptosis, and expression of cyclin D1 and cyclin E as potential biomarkers in tamoxifen-treated mammary tumors. Breast Cancer Res Treat 77(3):253–264PubMedCrossRef
90.
Sheth SS et al (2005) Thioredoxin-interacting protein deficiency disrupts the fasting-feeding metabolic transition. J Lipid Res 46(1):123–134PubMedCrossRef
91.
Sheth SS et al (2006) Hepatocellular carcinoma in Txnip-deficient mice. Oncogene 25(25):3528–3536PubMedCrossRef
92.
Yang X, Young LH, Voigt JM (1998) Expression of a vitamin D-regulated gene (VDUP-1) in untreated- and MNU-treated rat mammary tissue. Breast Cancer Res Treat 48(1):33–44PubMedCrossRef
93.
Willipinski-Stapelfeldt B et al (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11(22):8006–8014PubMedCrossRef
94.
Raviraj V, Fok S, Zhao J, Chien HY, Lyons JG, Thompson EW, Soon L (2011) Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices. BMC Cell Biology (submitted)
Metadata
Title
Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas
Authors
Vanisri Raviraj
Hui Zhang
Hsin-ya Chien
Louise Cole
Erik W. Thompson
Lilian Soon
Publication date
01-03-2012
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 3/2012
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-011-9450-4

Other articles of this Issue 3/2012

Clinical & Experimental Metastasis 3/2012 Go to the issue

Research Paper

Enhancement of metastatic ability by ectopic expression of ST6GalNAcI on a gastric cancer cell line in a mouse model

Research Paper

Palliative radiation therapy for pulmonary metastases from hepatocellular carcinoma

Research Paper

A novel mouse CD133 binding-peptide screened by phage display inhibits cancer cell motility in vitro

Research Paper

Regulation of HGF-mediated cell proliferation and invasion through NF-κB, JunB, and MMP-9 cascades in stomach cancer cells

Research Paper

The anti-adhesive mucin podocalyxin may help initiate the transperitoneal metastasis of high grade serous ovarian carcinoma

Research Paper

Erlotinib prevents experimental metastases of human small cell lung cancer cells with no epidermal growth factor receptor expression
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits