Top

Published in:

01-09-2011 | Preclinical study

Biologic role of activated leukocyte cell adhesion molecule overexpression in breast cancer cell lines and clinical tumor tissue

Authors: Sibyll Hein, Volkmar Müller, Nadine Köhler, Harriet Wikman, Sylke Krenkel, Thomas Streichert, Michaela Schweizer, Sabine Riethdorf, Volker Assmann, Maike Ihnen, Katrin Beck, Rana Issa, Fritz Jänicke, Klaus Pantel, Karin Milde-Langosch

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

The activated leukocyte cell adhesion molecule (ALCAM) is overexpressed in many mammary tumors, but controversial results about its role and prognostic impact in breast cancer have been reported. Therefore, we evaluated the biologic effects of ALCAM expression in two breast cancer cell lines and a larger cohort of mammary carcinomas. By stable transfections, MCF7 cells with ALCAM overexpression and MDA-MB231 cells with reduced ALCAM levels were generated and analyzed in functional assays and cDNA microarrays. In addition, an immunohistochemical study on 347 patients with breast cancer with long-term follow-up and analysis of disseminated tumor cells (DTCs) was performed. In both cell lines, high ALCAM expression was associated with reduced cell motility. In addition, ALCAM silencing in MDA-MB231 cells resulted in lower invasive potential, whereas high ALCAM expression was associated with increased apoptosis in both cell lines. Among genes which were differentially expressed in clones with altered ALCAM expression, there was an overlap of 15 genes between both cell lines, among them cathepsin D, keratin 7, gelsolin, and ets2 whose deregulation was validated by western blot analysis. In MDA-MB231 cells, we observed a correlation with VEGF expression which was validated by enzyme-linked immuno sorbent assay (ELISA). Our IHC results on primary breast carcinomas showed that ALCAM expression was associated with an estrogen receptor-positive phenotype. In addition, strong ALCAM immunostaining correlated with nodal involvement and the presence of tumor cells in bone marrow. By Kaplan–Meier analysis, strong ALCAM expression in ductal carcinomas correlated with shorter recurrence-free intervals (P = 0.048) and overall survival (OAS, P = 0.003). Our results indicate that the biologic role of ALCAM in breast cancer is complex, but overexpression might be relevant for outcome in ductal carcinomas.

Swart GW (2002) Activated leukocyte cell adhesion molecule (CD166/ALCAM): developmental and mechanistic aspects of cell clustering and cell migration. Eur J Cell Biol 81:313–321PubMedCrossRef

Uchida N, Yang Z, Combs J, Pourquie O, Nguyen M, Ramanathan R, Fu J, Welply A, Chen S, Weddell G et al (1997) The characterization, molecular cloning, and expression of a novel hematopoietic cell antigen from CD34+ human bone marrow cells. Blood 89:2706–2716PubMed

Ohneda O, Ohneda K, Arai F, Lee J, Miyamoto T, Fukushima Y, Dowbenko D, Lasky LA, Suda T (2001) ALCAM (CD166): its role in hematopoietic and endothelial development. Blood 98:2134–2142PubMedCrossRef

Masedunskas A, King JA, Tan F, Cochran R, Stevens T, Sviridov D, Ofori-Acquah SF (2006) Activated leukocyte cell adhesion molecule is a component of the endothelial junction involved in transendothelial monocyte migration. FEBS Lett 580:2637–2645PubMedCrossRef

Jezierska A, Matysiak W, Motyl T (2006) ALCAM/CD166 protects breast cancer cells against apoptosis and autophagy. Med Sci Monit 12:BR263–BR273PubMed

Ikeda K, Quertermous T (2004) Molecular isolation and characterization of a soluble isoform of activated leukocyte cell adhesion molecule that modulates endothelial cell function. J Biol Chem 279:55315–55323PubMedCrossRef

van Kilsdonk JW, Wilting RH, Bergers M, van Muijen GN, Schalkwijk J, van Kempen LC, Swart GW (2008) Attenuation of melanoma invasion by a secreted variant of activated leukocyte cell adhesion molecule. Cancer Res 68:3671–3679PubMedCrossRef

Degen WG, van Kempen LC, Gijzen EG, van Groningen JJ, van Kooyk Y, Bloemers HP, Swart GW (1998) MEMD, a new cell adhesion molecule in metastasizing human melanoma cell lines, is identical to ALCAM (activated leukocyte cell adhesion molecule). Am J Pathol 152:805–813PubMed

van Kempen LC, van den Oord JJ, van Muijen GN, Weidle UH, Bloemers HP, Swart GW (2000) Activated leukocyte cell adhesion molecule/CD166, a marker of tumor progression in primary malignant melanoma of the skin. Am J Pathol 156:769–774PubMedCrossRef

10.

Weichert W, Knosel T, Bellach J, Dietel M, Kristiansen G (2004) ALCAM/CD166 is overexpressed in colorectal carcinoma and correlates with shortened patient survival. J Clin Pathol 57:1160–1164PubMedCrossRef

11.

Sawhney M, Matta A, Macha MA, Kaur J, DattaGupta S, Shukla NK, Ralhan R (2009) Cytoplasmic accumulation of activated leukocyte cell adhesion molecule is a predictor of disease progression and reduced survival in oral cancer patients. Int J Cancer 124:2098–2105PubMedCrossRef

12.

Kahlert C, Weber H, Mogler C, Bergmann F, Schirmacher P, Kenngott HG, Matterne U, Mollberg N, Rahbari NN, Hinz U et al (2009) Increased expression of ALCAM/CD166 in pancreatic cancer is an independent prognostic marker for poor survival and early tumour relapse. Br J Cancer 101:457–464PubMedCrossRef

13.

Verma A, Shukla NK, Deo SV, Gupta SD, Ralhan R (2005) MEMD/ALCAM: a potential marker for tumor invasion and nodal metastasis in esophageal squamous cell carcinoma. Oncology 68:462–470PubMedCrossRef

14.

Choi S, Kobayashi M, Wang J, Habelhah H, Okada F, Hamada J, Moriuchi T, Totsuka Y, Hosokawa M (2000) Activated leukocyte cell adhesion molecule (ALCAM) and annexin II are involved in the metastatic progression of tumor cells after chemotherapy with Adriamycin. Clin Exp Metastasis 18:45–50PubMedCrossRef

15.

Kristiansen G, Pilarsky C, Wissmann C, Stephan C, Weissbach L, Loy V, Loening S, Dietel M, Rosenthal A (2003) ALCAM/CD166 is up-regulated in low-grade prostate cancer and progressively lost in high-grade lesions. Prostate 54:34–43PubMedCrossRef

16.

Mezzanzanica D, Fabbi M, Bagnoli M, Staurengo S, Losa M, Balladore E, Alberti P, Lusa L, Ditto A, Ferrini S et al (2008) Subcellular localization of activated leukocyte cell adhesion molecule is a molecular predictor of survival in ovarian carcinoma patients. Clin Cancer Res 14:1726–1733PubMedCrossRef

17.

King JA, Ofori-Acquah SF, Stevens T, Al-Mehdi AB, Fodstad O, Jiang WG (2004) Activated leukocyte cell adhesion molecule in breast cancer: prognostic indicator. Breast Cancer Res 6:R478–R487PubMedCrossRef

18.

Burkhardt M, Mayordomo E, Winzer KJ, Fritzsche F, Gansukh T, Pahl S, Weichert W, Denkert C, Guski H, Dietel M et al (2006) Cytoplasmic overexpression of ALCAM is prognostic of disease progression in breast cancer. J Clin Pathol 59:403–409PubMedCrossRef

19.

Davies SR, Dent C, Watkins G, King JA, Mokbel K, Jiang WG (2008) Expression of the cell to cell adhesion molecule, ALCAM, in breast cancer patients and the potential link with skeletal metastasis. Oncol Rep 19:555–561PubMed

20.

Ihnen M, Müller V, Wirtz RM, Schröder C, Krenkel S, Witzel I, Lisboa BW, Jänicke F, Milde-Langosch K (2008) Predictive impact of activated leukocyte cell adhesion molecule (ALCAM/CD166) in breast cancer. Breast Cancer Res Treat 112:419–427PubMedCrossRef

21.

Schröder C, Schumacher U, Müller V, Wirtz RM, Streichert T, Richter U, Wicklein D, Milde-Langosch K (2010) The transcription factor Fra-2 promotes mammary tumour progression by changing the adhesive properties of breast cancer cells. Eur J Cancer. doi:10.1016/j.ejca.2010.1002.1008

22.

Milde-Langosch K, Janke S, Wagner I, Schröder C, Streichert T, Bamberger AM, Jänicke F, Löning T (2008) Role of Fra-2 in breast cancer: influence on tumor cell invasion and motility. Breast Cancer Res Treat 107:337–347PubMedCrossRef

23.

Pantel K, Schlimok G, Angstwurm M, Weckermann D, Schmaus W, Gath H, Passlick B, Izbicki JR, Riethmuller G (1994) Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother 3:165–173PubMedCrossRef

24.

Bamberger A-M, Methner C, Lisboa BW, Städtler C, Schulte HM, Löning T, Milde-Langosch K (1999) Expression pattern of the AP-1 family in breast cancer: association of fosB expression with a well-differentiated, receptor-positive phenotype. Int J Cancer 84:553–558CrossRef

25.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100:229–235PubMedCrossRef

26.

Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802PubMedCrossRef

27.

Swart GW, Lunter PC, Kilsdonk JW, Kempen LC (2005) Activated leukocyte cell adhesion molecule (ALCAM/CD166): signaling at the divide of melanoma cell clustering and cell migration? Cancer Metastasis Rev 24:223–236PubMedCrossRef

28.

Liaudet-Coopman E, Beaujouin M, Derocq D, Garcia M, Glondu-Lassis M, Laurent-Matha V, Prebois C, Rochefort H, Vignon F (2006) Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett 237:167–179PubMedCrossRef

29.

Ohri SS, Vashishta A, Proctor M, Fusek M, Vetvicka V (2008) The propeptide of cathepsin D increases proliferation, invasion and metastasis of breast cancer cells. Int J Oncol 32:491–498PubMed

30.

Koslowski M, Sahin U, Mitnacht-Kraus R, Seitz G, Huber C, Tureci O (2007) A placenta-specific gene ectopically activated in many human cancers is essentially involved in malignant cell processes. Cancer Res 67:9528–9534PubMedCrossRef

31.

Willmarth NE, Baillo A, Dziubinski ML, Wilson K, Riese DJ II, Ethier SP (2009) Altered EGFR localization and degradation in human breast cancer cells with an amphiregulin/EGFR autocrine loop. Cell Signal 21:212–219PubMedCrossRef

32.

Tot T (2002) Cytokeratins 20 and 7 as biomarkers: usefulness in discriminating primary from metastatic adenocarcinoma. Eur J Cancer 38:758–763PubMedCrossRef

33.

Pratap J, Javed A, Languino LR, van Wijnen AJ, Stein JL, Stein GS, Lian JB (2005) The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. Mol Cell Biol 25:8581–8591PubMedCrossRef

34.

Shore P (2005) A role for Runx2 in normal mammary gland and breast cancer bone metastasis. J Cell Biochem 96:484–489PubMedCrossRef

35.

Akech J, Wixted JJ, Bedard K, van der Deen M, Hussain S, Guise TA, van Wijnen AJ, Stein JL, Languino LR, Altieri DC et al (2010) Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene 29:811–821PubMedCrossRef

36.

Singer S, Malz M, Herpel E, Warth A, Bissinger M, Keith M, Muley T, Meister M, Hoffmann H, Penzel R et al (2009) Coordinated expression of stathmin family members by far upstream sequence element-binding protein-1 increases motility in non-small cell lung cancer. Cancer Res 69:2234–2243PubMedCrossRef

37.

Bartkowiak K, Wieczorek M, Buck F, Harder S, Moldenhauer J, Effenberger KE, Pantel K, Peter-Katalinic J, Brandt BH (2009) Two-dimensional differential gel electrophoresis of a cell line derived from a breast cancer micrometastasis revealed a stem/progenitor cell protein profile. J Proteome Res 8:2004–2014PubMedCrossRef

38.

Ioachim E, Charchanti A, Briasoulis E, Karavasilis V, Tsanou H, Arvanitis DL, Agnantis NJ, Pavlidis N (2002) Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. Eur J Cancer 38:2362–2370PubMedCrossRef

39.

Helleman J, Jansen MP, Ruigrok-Ritstier K, van Staveren IL, Look MP, Meijer-van Gelder ME, Sieuwerts AM, Klijn JG, Sleijfer S, Foekens JA et al (2008) Association of an extracellular matrix gene cluster with breast cancer prognosis and endocrine therapy response. Clin Cancer Res 14:5555–5564PubMedCrossRef

40.

Buggy Y, Maguire TM, McDermott E, Hill AD, O’Higgins N, Duffy MJ (2006) Ets2 transcription factor in normal and neoplastic human breast tissue. Eur J Cancer 42:485–491PubMedCrossRef

41.

Swanton C, Downward J (2008) Unraveling the complexity of endocrine resistance in breast cancer by functional genomics. Cancer Cell 13:83–85PubMedCrossRef

42.

Chen S, McLean S, Carter DE, Leask A (2007) The gene expression profile induced by Wnt 3a in NIH 3T3 fibroblasts. J Cell Commun Signal 1:175–183PubMedCrossRef

43.

Gavert N, Conacci-Sorrell M, Gast D, Schneider A, Altevogt P, Brabletz T, Ben-Ze’ev A (2005) L1, a novel target of beta-catenin signaling, transforms cells and is expressed at the invasive front of colon cancers. J Cell Biol 168:633–642PubMedCrossRef

44.

Meier F, Busch S, Gast D, Goppert A, Altevogt P, Maczey E, Riedle S, Garbe C, Schittek B (2006) The adhesion molecule L1 (CD171) promotes melanoma progression. Int J Cancer 119:549–555PubMedCrossRef

45.

Schröder C, Schumacher U, Fogel M, Feuerhake F, Müller V, Wirtz RM, Altevogt P, Krenkel S, Jänicke F, Milde-Langosch K (2009) Expression and prognostic value of L1-CAM in breast cancer. Oncol Rep 22:1109–1117PubMed

46.

Jezierska A, Olszewski WP, Pietruszkiewicz J, Olszewski W, Matysiak W, Motyl T (2006) Activated leukocyte cell adhesion molecule (ALCAM) is associated with suppression of breast cancer cells invasion. Med Sci Monit 12:BR245–BR256PubMed

47.

Pantel K, Alix-Panabieres C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6:339–351PubMedCrossRef

48.

Wiiger MT, Gehrken HB, Fodstad O, Maelandsmo GM, Andersson Y (2010) A novel human recombinant single-chain antibody targeting CD166/ALCAM inhibits cancer cell invasion in vitro and in vivo tumour growth. Cancer Immunol Immunother 59:1665–1674PubMedCrossRef

Title: Biologic role of activated leukocyte cell adhesion molecule overexpression in breast cancer cell lines and clinical tumor tissue
Authors: Sibyll Hein
Volkmar Müller
Nadine Köhler
Harriet Wikman
Sylke Krenkel
Thomas Streichert
Michaela Schweizer
Sabine Riethdorf
Volker Assmann
Maike Ihnen
Katrin Beck
Rana Issa
Fritz Jänicke
Klaus Pantel
Karin Milde-Langosch
Publication date: 01-09-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-1219-y

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

TNF-alpha polymorphisms and breast cancer

Association of XPC polymorphisms with breast cancer risk

Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer

Ras-related protein 1 and the insulin-like growth factor type I receptor are associated with risk of progression in patients diagnosed with carcinoma in situ

Keynote webinar | Spotlight on antibody–drug conjugates in cancer