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01.11.2014 | Original paper

The presence of clustered circulating tumor cells (CTCs) and circulating cytokines define an aggressive phenotype in metastatic colorectal cancer

verfasst von: Rosa Divella, Antonella Daniele, Ines Abbate, Antonia Bellizzi, Eufemia Savino, Giovanni Simone, Grazia Giannone, Francesco Giuliani, Vito Fazio, Gennaro Gadaleta-Caldarola, Cosimo Damiano Gadaleta, Ivan Lolli, Carlo Sabbà, Antonio Mazzocca

Erschienen in: Cancer Causes & Control | Ausgabe 11/2014

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Abstract

Purpose

Colon carcinoma is a malignant tumor showing a marked preference to metastasize to distant organs. The presence of circulating tumor cells (CTCs) in the peripheral blood is a prerequisite for the formation of distant metastases. However, whether circulating cytokines are linked to the circulation of tumor cells, as individual cells or clusters, remain unclear. In this study, we investigated the circulating levels of TGF-beta, CXCL1, VEGF and PAI-1 as potential bioindicators of the presence of CTCs in patients with metastatic colon cancer.

Methods

Circulating tumor cells (CTCs) were isolated from peripheral blood by immunomagnetic separation and phenotypically characterized in a cohort of 103 patients with metastatic colon cancer. TGF-beta, CXCL1, VEGF and PAI-1 concentrations were determined by immunoassay in plasma samples from the same patients.

Results

We detected two different populations of CTCs, single cells or clusters in patients with metastatic colon cancer. Importantly, we found that the presence of clustered CTCs is significantly associated with elevated circulating levels of TGF-beta and CXCL1 and with reduced overall survival. Finally, we observed that circulating levels of cytokines are differently associated with the two populations of CTCs.

Conclusions

Taken together, these findings show that detection of clustered CTCs represents a negative prognostic factor in patients with metastatic colon cancer. The presence of clustered CTCs is associated with elevated circulating levels of cytokines such as TGF-beta and CXCL1. This suggests an additional role for circulating cytokines as predictive tool for cancer prognosis and diagnosis of minimal residual disease as well as assessment of tumor sensitivity to anticancer therapy.

Bardhan K, Liu K (2013) Epigenetics and colorectal cancer pathogenesis. Cancers 5(2):676–713PubMedCrossRefPubMedCentral

Marudanayagam R, Ramkumar K, Shanmugam V, Langman G, Rajesh P, Coldham C, Bramhall SR, Mayer D, Buckels J, Mirza DF (2009) Long-term outcome after sequential resections of liver and lung metastases from colorectal carcinoma. HPB (Oxford) 11(8):671–676CrossRef

Shah SA, Haddad R, Al-Sukhni W, Kim RD, Greig PD, Grant DR, Taylor BR, Langer B, Gallinger S, Wei AC (2006) Surgical resection of hepatic and pulmonary metastases from colorectal carcinoma. J Am Coll Surg 202(3):468–475PubMedCrossRef

Miller G, Biernacki P, Kemeny NE, Gonen M, Downey R, Jarnagin WR, D’Angelica M, Fong Y, Blumgart LH, DeMatteo RP (2007) Outcomes after resection of synchronous or metachronous hepatic and pulmonary colorectal metastases. J Am Coll Surg 205(2):231–238PubMedCrossRef

Paget S (1889) The distribution of secondary growth in cancer of the breast. Lancet 1:571–573CrossRef

Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458PubMedCrossRef

Balzer EM, Konstantopoulos K (2012) Intercellular adhesion: mechanisms for growth and metastasis of epithelial cancers. Wiley Interdiscip Rev Syst Biol Med 4(2):171–181PubMedCrossRef

Brooks SA, Lomax-Browne HJ, Carter TM, Kinch CE, Hall DM (2010) Molecular interactions in cancer cell metastasis. Acta Histochem 112(1):3–25PubMedCrossRef

Gassmann P, Haier J (2008) The tumor cell-host organ interface in the early onset of metastatic organ colonization. Clin Exp Metastasis 25(2):171–181PubMedCrossRef

10.

Gassmann P, Enns A, Haier J (2004) Role of tumor cell adhesion and migration in organ specific metastasis formation. Onkologie 27(6):577–582PubMedCrossRef

11.

Richmond A (2010) Chemokine modulation of the tumor microenvironment. Pigment Cell Melanoma Res 23(3):312–313PubMedCrossRefPubMedCentral

12.

Spano D, Heckc C, De Antonellis P, Christofori G, Zollo M (2012) Molecular networks that regulate cancer metastasis. Semi Cancer Biol 22:234–249CrossRef

13.

Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4:540–550PubMedCrossRef

14.

Mazzocca A, Fransvea E, Dituri F, Lupo L, Antonaci S, Giannelli G (2010) Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma. Hepatology 51(2):523–534PubMedCrossRef

15.

Divella R, Daniele A, Gadaleta C, Tufaro A, Venneri MT, Paradiso A, Quaranta M (2012) Circulating transforming growth factor-β and epidermal growth factor receptor as related to virus infection in liver carcinogenesis. Anticancer Res 32(1):141–145PubMed

16.

Ogata H, Sekikawa A, Yamagishi H, Ichikawa K, Tomita S, Imura J, Ito Y, Fujita M, Tsubaki M, Kato H, Fujimori T, Fukui H (2010) GROα promotes invasion of colorectal cancer cells. Oncol Rep 24(6):1479–1486PubMed

17.

Imamura T, Hikita A, Inoue Y (2012) The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis. Breast Cancer 19(2):118–124PubMedCrossRef

18.

Divella R, Lacalamita R, Tommasi S, Coviello M, Daniele A, Garrisi VM, Abbate I, Simone G, Gadaleta C, Paradiso A, Quaranta M (2008) PAI-1, t-PA and circulating hTERT DNA as related to virus infection in liver carcinogenesis. Anticancer Res 28(1A):223–228PubMed

19.

Halamkova J, Kiss I, Pavlovsky Z, Tomasek J, Jarkovsky J, Cech Z, Tucek S, Hanakova L, Moulis M, Zavrelova J, Man M, Benda P, Robek O, Kala Z, Penka M (2011) Clinical significance of the plasminogen activator system in relation to grade of tumor and treatment response in colorectal carcinoma patients. Neoplasma 58(5):377–385PubMedCrossRef

20.

Xu B, Shen F, Cao J, Jia L (2013) Angiogenesis in liver metastasis of colorectal carcinoma. Front Biosci (Landmark Ed) 18:1435–1443CrossRef

21.

Liu W, Xu J, Wang M, Wang Q, Bi Y, Han M (2011) Tumor derived vascular endothelial growth factor (VEGF-a) facilitates tumor metastasis through the VEGF-VEGFR1 signaling pathway. Int J Oncol 39:1213–1220PubMed

22.

Bellizzi A, Sebastian S, Ceglia P, Centonze M, Divella R, Manzillo EF, Azzariti A, Silvestris N, Montemurro S, Caliandro C, De Luca R, Cicero G, Rizzo S, Russo A, Quaranta M, Simone G, Paradiso A (2013) Co-expression of CD133 (+)/CD44 (+) in human colon cancer and liver metastasis. J Cell Physiol 228(2):408–415PubMedCrossRef

23.

Schluter K, Gassmann P, Enns A, Korb T, Hemping-Bovenkerk A, Holzen J, Haier J (2006) Organ-specific metastatic tumor cell adhesion and extravasation of colon carcinoma cells with different metastatic potential. Am J Pathol 169(3):1064–1073PubMedCrossRefPubMedCentral

24.

Sleemana JP, Christofori G, Fodded R, Collarde JG, Berx G, Decraeneh C, Rüegg C (2012) Concepts of metastasis in flux: the stromal progression model. Semin Cancer Biol 22:174–186CrossRef

25.

Lorusso G, Rüegg C (2012) New insights into the mechanisms of organ-specific breast cancer metastasis. Semin Cancer Biol 22:226–233PubMedCrossRef

26.

Catalano V, Turdo A, Di Franco S, Dieli F, Todaro M, Stassi G (2013) Tumor and its microenvironment: a synergistic interplay. Semin Cancer Biol 23:522–532

27.

Divella R, Daniele A, Savino E, Palma F, Bellizzi A, Giotta F, Simone G, Lioce M, Quaranta M, Paradiso A, Mazzocca A (2013) Circulating levels of transforming growth factor-beta (TGF-beta) and chemokine (C-X-C motif) ligand-1 (CXCL1) as predictors of distant seeding of circulating tumor cells in patients with metastatic breast cancer. Anticancer Res 33(4):1491–1497PubMed

28.

Lazennec G, Richmond A (2010) Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol Med 16(3):133–144PubMedCrossRefPubMedCentral

29.

Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova Todorova K, Leversha M, Hogg N, Seshan VE, Norton L, Brogi E, Massagué J (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150(1):165–178PubMedCrossRefPubMedCentral

30.

Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, Ward T, Blackhall FH, Dive C (2012) Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol 30(5):525–532PubMedCrossRef

31.

Kochetkova M, Kumar S, McColl SR (2009) Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells. Cell Death Differ 16(5):664–673PubMedCrossRef

32.

Muñoz NM, Baek JY, Grady WM (2008) TGF-beta has paradoxical and context dependent effects on proliferation and anoikis in human colorectal cancer cell lines. Growth Factors 26(5):254–262PubMedCrossRefPubMedCentral

33.

Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G (2009) Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology 50(4):1140–1151PubMedCrossRef

34.

Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374PubMedCrossRef

35.

Colussi D, Brandi G, Bazzoli F, Ricciardiello L (2013) Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention. Int J Mol Sci 14(8):16365–16385PubMedCrossRefPubMedCentral

36.

Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, Yamauchi M, Imamura Y, Qian ZR, Baba Y, Shima K, Sun R, Nosho K, Meyerhardt JA, Giovannucci E, Fuchs CS, Chan AT, Ogino S (2012) Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367(17):1596–1606PubMedCrossRefPubMedCentral

37.

Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, Liao X, Waldron L, Hoshida Y, Huttenhower C, Chan AT, Giovannucci E, Fuchs C, Ogino S (2012) Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 61(6):847–854PubMedCrossRefPubMedCentral

38.

Yamauchi M, Lochhead P, Morikawa T, Huttenhower C, Chan AT, Giovannucci E, Fuchs C, Ogino S (2012) Colorectal cancer: a tale of two sides or a continuum? Gut 6:794–797CrossRef

39.

Rosty C, Young JP, Walsh MD, Clendenning M, Walters RJ, Pearson S, Pavluk E, Nagler B, Pakenas D, Jass JR, Jenkins MA, Win AK, Southey MC, Parry S, Hopper JL, Giles GG, Williamson E, English DR, Buchanan DD (2013) Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features. Mod Pathol 26(6):825–834PubMedCrossRef

Titel: The presence of clustered circulating tumor cells (CTCs) and circulating cytokines define an aggressive phenotype in metastatic colorectal cancer
verfasst von: Rosa Divella
Antonella Daniele
Ines Abbate
Antonia Bellizzi
Eufemia Savino
Giovanni Simone
Grazia Giannone
Francesco Giuliani
Vito Fazio
Gennaro Gadaleta-Caldarola
Cosimo Damiano Gadaleta
Ivan Lolli
Carlo Sabbà
Antonio Mazzocca
Publikationsdatum: 01.11.2014
Verlag: Springer International Publishing
Erschienen in: Cancer Causes & Control / Ausgabe 11/2014
Print ISSN: 0957-5243
Elektronische ISSN: 1573-7225
DOI: https://doi.org/10.1007/s10552-014-0457-4

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The presence of clustered circulating tumor cells (CTCs) and circulating cytokines define an aggressive phenotype in metastatic colorectal cancer

Abstract

Purpose

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Results

Conclusions

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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