Skip to main content
Erschienen in: Medical Molecular Morphology 2/2014

01.06.2014 | Review

Invasion and metastasis of renal cell carcinoma

verfasst von: Shuji Mikami, Mototsugu Oya, Ryuichi Mizuno, Takeo Kosaka, Ken-ichi Katsube, Yasunori Okada

Erschienen in: Medical Molecular Morphology | Ausgabe 2/2014

Einloggen, um Zugang zu erhalten

Abstract

Renal cell carcinoma (RCC) represents over 80 % of kidney cancer, and about 30 % of the patients with RCC develop metastasis after the surgery. Invasion of basement membrane (BM) and extracellular matrix (ECM) is an essential event in tumor invasion and metastasis. Matrix metalloproteinases (MMPs), which digest the main components of BM and ECM, are expressed in RCC. Heparanase, which degrades heparan sulfate proteoglycans, is predominantly expressed in high-grade RCCs with a positive correlation with pathological tumor stage and poor prognosis. Bone metastasis is common among the patients with RCC, and increased osteoclastic activity was observed at metastatic sites. Receptor activator of nuclear factor κB ligand (RANKL), which plays an important role in osteoclastogenesis, is predominantly expressed in high-grade RCC and its expression level is associated with bone metastasis and prognosis. Epithelial-mesenchymal transition (EMT), a switch of epithelial cells to sarcomatoid phenotype, is considered to be critical step during metastasis, and Snail, a major regulator of EMT, is predominantly expressed in high-grade RCC, and high Snail expression is a worse prognostic factor. Accordingly, heparanase, RANKL and Snail may be targets for the development of anti-tumor therapies for RCCs.
Literatur
1.
Zurück zum Zitat Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds) (2005) World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. IARC Press, Lyon Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds) (2005) World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. IARC Press, Lyon
2.
Zurück zum Zitat Jung K, Lein M, Laube C, Lichtinghagen R (2001) Blood specimen collection methods influence the concentration and the diagnostic validity of matrix metalloproteinase 9 in blood. Clin Chim Acta 314:241–244PubMedCrossRef Jung K, Lein M, Laube C, Lichtinghagen R (2001) Blood specimen collection methods influence the concentration and the diagnostic validity of matrix metalloproteinase 9 in blood. Clin Chim Acta 314:241–244PubMedCrossRef
3.
Zurück zum Zitat Fuhrman SA, Lasky LC, Limas C (1982) Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655–663PubMedCrossRef Fuhrman SA, Lasky LC, Limas C (1982) Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 6:655–663PubMedCrossRef
4.
Zurück zum Zitat Jung K, Nowak L, Lein M, Priem F, Schnorr D, Loening SA (1997) Matrix metalloproteinases 1 and 3, tissue inhibitor of metalloproteinase-1 and the complex of metalloproteinase-1/tissue inhibitor in plasma of patients with prostate cancer. Int J Cancer 74:220–223PubMedCrossRef Jung K, Nowak L, Lein M, Priem F, Schnorr D, Loening SA (1997) Matrix metalloproteinases 1 and 3, tissue inhibitor of metalloproteinase-1 and the complex of metalloproteinase-1/tissue inhibitor in plasma of patients with prostate cancer. Int J Cancer 74:220–223PubMedCrossRef
5.
Zurück zum Zitat Janzen NK, Kim HL, Figlin RA, Belldegrun AS (2003) Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 30:843–852PubMedCrossRef Janzen NK, Kim HL, Figlin RA, Belldegrun AS (2003) Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 30:843–852PubMedCrossRef
6.
Zurück zum Zitat Suzuki K, Mizuno R, Mikami S, Tanaka N, Kanao K, Kikuchi E, Miyajima A, Nakagawa K, Oya M (2012) Prognostic significance of high nuclear grade in patients with pathologic T1a renal cell carcinoma. Jpn J Clin Oncol 42:831–835PubMedCrossRef Suzuki K, Mizuno R, Mikami S, Tanaka N, Kanao K, Kikuchi E, Miyajima A, Nakagawa K, Oya M (2012) Prognostic significance of high nuclear grade in patients with pathologic T1a renal cell carcinoma. Jpn J Clin Oncol 42:831–835PubMedCrossRef
8.
Zurück zum Zitat Engbring JA, Kleinman HK (2003) The basement membrane matrix in malignancy. J Pathol 200:465–470PubMedCrossRef Engbring JA, Kleinman HK (2003) The basement membrane matrix in malignancy. J Pathol 200:465–470PubMedCrossRef
9.
Zurück zum Zitat Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270PubMedCrossRef Chambers AF, Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89:1260–1270PubMedCrossRef
10.
Zurück zum Zitat Curran S, Murray GI (2000) Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer 36:1621–1630PubMedCrossRef Curran S, Murray GI (2000) Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer 36:1621–1630PubMedCrossRef
11.
Zurück zum Zitat Shiomi T, Lemaitre V, D’Armiento J, Okada Y (2010) Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases. Pathol Int 60:477–496PubMedCentralPubMedCrossRef Shiomi T, Lemaitre V, D’Armiento J, Okada Y (2010) Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases. Pathol Int 60:477–496PubMedCentralPubMedCrossRef
12.
Zurück zum Zitat Kugler A, Hemmerlein B, Thelen P, Kallerhoff M, Radzun HJ, Ringert RH (1998) Expression of metalloproteinase 2 and 9 and their inhibitors in renal cell carcinoma. J Urol 160:1914–1918PubMedCrossRef Kugler A, Hemmerlein B, Thelen P, Kallerhoff M, Radzun HJ, Ringert RH (1998) Expression of metalloproteinase 2 and 9 and their inhibitors in renal cell carcinoma. J Urol 160:1914–1918PubMedCrossRef
13.
Zurück zum Zitat Lein M, Jung K, Laube C, Hubner T, Winkelmann B, Stephan C, Hauptmann S, Rudolph B, Schnorr D, Loening SA (2000) Matrix-metalloproteinases and their inhibitors in plasma and tumor tissue of patients with renal cell carcinoma. Int J Cancer 85:801–804PubMedCrossRef Lein M, Jung K, Laube C, Hubner T, Winkelmann B, Stephan C, Hauptmann S, Rudolph B, Schnorr D, Loening SA (2000) Matrix-metalloproteinases and their inhibitors in plasma and tumor tissue of patients with renal cell carcinoma. Int J Cancer 85:801–804PubMedCrossRef
14.
Zurück zum Zitat Vlodavsky I, Beckhove P, Lerner I, Pisano C, Meirovitz A, Ilan N, Elkin M (2012) Significance of heparanase in cancer and inflammation. Cancer Microenviron 5:115–832PubMedCentralPubMedCrossRef Vlodavsky I, Beckhove P, Lerner I, Pisano C, Meirovitz A, Ilan N, Elkin M (2012) Significance of heparanase in cancer and inflammation. Cancer Microenviron 5:115–832PubMedCentralPubMedCrossRef
15.
Zurück zum Zitat Nakajima M, Irimura T, Di Ferrante N, Nicolson GL (1984) Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase. J Biol Chem 259:2283–2290PubMed Nakajima M, Irimura T, Di Ferrante N, Nicolson GL (1984) Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase. J Biol Chem 259:2283–2290PubMed
16.
Zurück zum Zitat Dall’Oglio MF, Ribeiro-Filho LA, Antunes AA, Crippa A, Nesrallah L, Goncalves PD, Leite KR, Srougi M (2007) Microvascular tumor invasion, tumor size and Fuhrman grade: a pathological triad for prognostic evaluation of renal cell carcinoma. J Urol 178:425–428PubMedCrossRef Dall’Oglio MF, Ribeiro-Filho LA, Antunes AA, Crippa A, Nesrallah L, Goncalves PD, Leite KR, Srougi M (2007) Microvascular tumor invasion, tumor size and Fuhrman grade: a pathological triad for prognostic evaluation of renal cell carcinoma. J Urol 178:425–428PubMedCrossRef
17.
Zurück zum Zitat Mikami S, Oya M, Shimoda M, Mizuno R, Ishida M, Kosaka T, Mukai M, Nakajima M, Okada Y (2008) Expression of heparanase in renal cell carcinomas: implications for tumor invasion and prognosis. Clin Cancer Res 14:6055–6061PubMedCrossRef Mikami S, Oya M, Shimoda M, Mizuno R, Ishida M, Kosaka T, Mukai M, Nakajima M, Okada Y (2008) Expression of heparanase in renal cell carcinomas: implications for tumor invasion and prognosis. Clin Cancer Res 14:6055–6061PubMedCrossRef
18.
Zurück zum Zitat Zekri J, Ahmed N, Coleman RE, Hancock BW (2001) The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 19:379–382PubMed Zekri J, Ahmed N, Coleman RE, Hancock BW (2001) The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 19:379–382PubMed
19.
Zurück zum Zitat Dougall WC (2012) Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin Cancer Res 18:326–335PubMedCrossRef Dougall WC (2012) Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin Cancer Res 18:326–335PubMedCrossRef
20.
Zurück zum Zitat Wittrant Y, Theoleyre S, Chipoy C, Padrines M, Blanchard F, Heymann D, Redini F (2004) RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta 1704:49–57PubMed Wittrant Y, Theoleyre S, Chipoy C, Padrines M, Blanchard F, Heymann D, Redini F (2004) RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochim Biophys Acta 1704:49–57PubMed
21.
Zurück zum Zitat Zhang J, Dai J, Yao Z, Lu Y, Dougall W, Keller ET (2003) Soluble receptor activator of nuclear factor κB Fc diminishes prostate cancer progression in bone. Cancer Res 63:7883–7890PubMed Zhang J, Dai J, Yao Z, Lu Y, Dougall W, Keller ET (2003) Soluble receptor activator of nuclear factor κB Fc diminishes prostate cancer progression in bone. Cancer Res 63:7883–7890PubMed
22.
Zurück zum Zitat Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696PubMedCrossRef Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM (2006) Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440:692–696PubMedCrossRef
23.
Zurück zum Zitat Wittrant Y, Lamoureux F, Mori K, Riet A, Kamijo A, Heymann D, Redini F (2006) RANKL directly induces bone morphogenetic protein-2 expression in RANK-expressing POS-1 osteosarcoma cells. Int J Oncol 28:261–269PubMed Wittrant Y, Lamoureux F, Mori K, Riet A, Kamijo A, Heymann D, Redini F (2006) RANKL directly induces bone morphogenetic protein-2 expression in RANK-expressing POS-1 osteosarcoma cells. Int J Oncol 28:261–269PubMed
24.
Zurück zum Zitat Mikami S, Katsube K, Oya M, Ishida M, Kosaka T, Mizuno R, Mochizuki S, Ikeda T, Mukai M, Okada Y (2009) Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol 218:530–539PubMedCrossRef Mikami S, Katsube K, Oya M, Ishida M, Kosaka T, Mizuno R, Mochizuki S, Ikeda T, Mukai M, Okada Y (2009) Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J Pathol 218:530–539PubMedCrossRef
25.
Zurück zum Zitat Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A, Jun S (2012) Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082–3092PubMedCrossRef Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A, Jun S (2012) Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082–3092PubMedCrossRef
26.
Zurück zum Zitat Keizman D, Ish-Shalom M, Maimon N, Gottfried M (2013) Are bisphosphonates an indispensable tool in the era of targeted therapy for renal cell carcinoma and bone metastases? World J Urol (in press) Keizman D, Ish-Shalom M, Maimon N, Gottfried M (2013) Are bisphosphonates an indispensable tool in the era of targeted therapy for renal cell carcinoma and bone metastases? World J Urol (in press)
27.
Zurück zum Zitat Kijima T, Fujii Y, Suyama T, Okubo Y, Yamamoto S, Masuda H, Yonese J, Fukui I (2009) Radiotherapy to bone metastases from renal cell carcinoma with or without zoledronate. BJU Int 103:620–624PubMedCrossRef Kijima T, Fujii Y, Suyama T, Okubo Y, Yamamoto S, Masuda H, Yonese J, Fukui I (2009) Radiotherapy to bone metastases from renal cell carcinoma with or without zoledronate. BJU Int 103:620–624PubMedCrossRef
28.
Zurück zum Zitat Nieto MA (2011) The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 27:347–376PubMedCrossRef Nieto MA (2011) The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 27:347–376PubMedCrossRef
29.
Zurück zum Zitat Grunert S, Jechlinger M, Beug H (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4:657–665PubMedCrossRef Grunert S, Jechlinger M, Beug H (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4:657–665PubMedCrossRef
30.
Zurück zum Zitat Canel M, Serrels A, Frame MC, Brunton VG (2013) E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci 126:393–401PubMedCrossRef Canel M, Serrels A, Frame MC, Brunton VG (2013) E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci 126:393–401PubMedCrossRef
31.
Zurück zum Zitat Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746PubMedCrossRef Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746PubMedCrossRef
32.
Zurück zum Zitat Alves CC, Carneiro F, Hoefler H, Becker KF (2009) Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers. Front Biosci 14:3035–3050CrossRef Alves CC, Carneiro F, Hoefler H, Becker KF (2009) Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers. Front Biosci 14:3035–3050CrossRef
33.
Zurück zum Zitat Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2:84–89PubMedCrossRef Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2:84–89PubMedCrossRef
34.
Zurück zum Zitat Katagiri A, Watanabe R, Tomita Y (1995) E-cadherin expression in renal cell cancer and its significance in metastasis and survival. Br J Cancer 71:376–379PubMedCentralPubMedCrossRef Katagiri A, Watanabe R, Tomita Y (1995) E-cadherin expression in renal cell cancer and its significance in metastasis and survival. Br J Cancer 71:376–379PubMedCentralPubMedCrossRef
35.
Zurück zum Zitat Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A, Raval R, O’Brien TS, Maxwell PH (2006) Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 66:3567–3575PubMedCrossRef Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A, Raval R, O’Brien TS, Maxwell PH (2006) Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 66:3567–3575PubMedCrossRef
36.
Zurück zum Zitat Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, Kim WY, Saravanan A, Maynard MA, Gervais ML, Sufan RI, Roberts AM, Wilson LA, Betten M, Vandewalle C, Berx G, Marsden PA, Irwin MS, Teh BT, Jewett MA, Ohh M (2007) VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol 27:157–169PubMedCentralPubMedCrossRef Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, Kim WY, Saravanan A, Maynard MA, Gervais ML, Sufan RI, Roberts AM, Wilson LA, Betten M, Vandewalle C, Berx G, Marsden PA, Irwin MS, Teh BT, Jewett MA, Ohh M (2007) VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol 27:157–169PubMedCentralPubMedCrossRef
37.
Zurück zum Zitat Harten SK, Shukla D, Barod R, Hergovich A, Balda MS, Matter K, Esteban MA, Maxwell PH (2009) Regulation of renal epithelial tight junctions by the von Hippel–Lindau tumor suppressor gene involves occludin and claudin 1 and is independent of E-cadherin. Mol Biol Cell 20:1089–1101PubMedCentralPubMedCrossRef Harten SK, Shukla D, Barod R, Hergovich A, Balda MS, Matter K, Esteban MA, Maxwell PH (2009) Regulation of renal epithelial tight junctions by the von Hippel–Lindau tumor suppressor gene involves occludin and claudin 1 and is independent of E-cadherin. Mol Biol Cell 20:1089–1101PubMedCentralPubMedCrossRef
38.
Zurück zum Zitat Mikami S, Katsube K, Oya M, Ishida M, Kosaka T, Mizuno R, Mukai M, Okada Y (2011) Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis. Lab Invest 91:1443–1458PubMedCrossRef Mikami S, Katsube K, Oya M, Ishida M, Kosaka T, Mizuno R, Mukai M, Okada Y (2011) Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis. Lab Invest 91:1443–1458PubMedCrossRef
Metadaten
Titel
Invasion and metastasis of renal cell carcinoma
verfasst von
Shuji Mikami
Mototsugu Oya
Ryuichi Mizuno
Takeo Kosaka
Ken-ichi Katsube
Yasunori Okada
Publikationsdatum
01.06.2014
Verlag
Springer Japan
Erschienen in
Medical Molecular Morphology / Ausgabe 2/2014
Print ISSN: 1860-1480
Elektronische ISSN: 1860-1499
DOI
https://doi.org/10.1007/s00795-013-0064-6

Weitere Artikel der Ausgabe 2/2014

Medical Molecular Morphology 2/2014 Zur Ausgabe

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Open Access Biomarker Leitthema

Um auch an kleinen Gewebeproben zuverlässige und reproduzierbare Ergebnisse zu gewährleisten ist eine strenge Qualitätskontrolle in jedem Schritt des Arbeitsablaufs erforderlich. Eine nicht ordnungsgemäße Prüfung oder Behandlung des …

Vergleichende Pathologie in der onkologischen Forschung

Pathologie Leitthema

Die vergleichende experimentelle Pathologie („comparative experimental pathology“) ist ein Fachbereich an der Schnittstelle von Human- und Veterinärmedizin. Sie widmet sich der vergleichenden Erforschung von Gemeinsamkeiten und Unterschieden von …

Gastrointestinale Stromatumoren

Open Access GIST CME-Artikel

Gastrointestinale Stromatumoren (GIST) stellen seit über 20 Jahren ein Paradigma für die zielgerichtete Therapie mit Tyrosinkinaseinhibitoren dar. Eine elementare Voraussetzung für eine mögliche neoadjuvante oder adjuvante Behandlung bei …

Personalisierte Medizin in der Onkologie

Aufgrund des erheblichen technologischen Fortschritts in der molekularen und genetischen Diagnostik sowie zunehmender Erkenntnisse über die molekulare Pathogenese von Krankheiten hat in den letzten zwei Jahrzehnten ein grundlegender …