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COMMENTARY |
Cell Biology and Preclinical Models Unit, National Cancer Institute, INT-Fondazione Pascale, Via Mariano Semmola, 80131 Naples, Italy
1 Cancer Biology Laboratory, Research School of Biosciences, University of Kent, Canterbury CT2 7NJ, United Kingdom
(Requests for offprints should be addressed to N Normanno; Email: nicnorm{at}yahoo.com)
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Abstract |
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 Top Abstract References |
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Epidermal growth factor receptor (EGFR) and its ligands are expressed in all cell types with the exception of cells of haematological origin (Salomon et al. 1995, Normanno et al. 2005a). More importantly, expression of these proteins has been found in the majority of human carcinomas. Pre-clinical studies have also demonstrated that autocrine and/or paracrine loops involving EGFR and EGF-like peptides regulate the growth, survival and ability to form metastases of tumour cells. Following this observation, a number of drugs directed against EGFR have been developed, and are currently under clinical investigation or have been approved for treatment of selected tumour types. Among these, tyrosine kinase inhibitors (TKIs) of EGFR have been shown to efficiently block in vitro and in vivo the activation of the target receptor, and to significantly inhibit tumour growth in experimental models (Normanno et al. 2003). However, clinical studies have generally shown poor activity of these drugs when used as monotherapy in heavily pre-treated cancer patients. The low efficacy of these drugs is likely to be due to the lack of appropriate criteria for selection of patients, although this is an active area of research (Chan et al. 2006).
The paper by Angelucci et al. published in the current issue of Endocrine-Related Cancer suggests a potential, novel application of EGFR-TKIs in the treatment of bone metastases. In this study, Angelucci and co-workers demonstrate that treatment with gefitinib significantly reduces the ability of a highly metastatic clone of PC3 prostate cancer cells (PCb2 cells) to form bone metastases. Different mechanisms seem to be involved in this phenomenon. The urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) system and matrix metalloproteinases (MMPs) have been shown to be involved in the invasive ability of tumour cells and in the formation of bone metastases (Guise & Mundy 1998, Nemeth et al. 2002). Treatment with gefitinib significantly reduced the expression and activation of uPA and MMP-9 in prostate cancer cells, and this was associated with a significant decrease in the invasive ability of PCb2 cells. Furthermore, PCb2 cells were found to express higher levels of uPAR as compared with parental PC3 cells, and treatment with uPA increased significantly the levels of activation of the EGFR in PCb2 cells. These findings suggest that the cross-talk between the uPA/uPAR system and the EGFR might sustain the ability of these highly metastatic cells to form bone metastases, and that gefitinib is able to significantly block this mechanism.
The effects of gefitinib on the formation of bone metastases might also be related to its ability to interfere with osteoclast differentiation and activation. The main mechanism responsible for bone destruction in cancer patients is tumour-mediated stimulation of osteoclastic bone resorption (Roodman 2001) (Fig. 1
). However, most osteotropicfactors produced by tumour cells act indirectly by binding to accessory cells of the bone marrow microenvironment (Roodman 2001). This heterogeneous cell compartment consists of endothelial cells, as well as mesenchymal stem cells (MSCs), which maintain a level of self renewal and give rise to different specialized connective tissue cells including ‘reticular cells’ and osteoblasts (Clark & Keating 1995, Deans & Moseley 2000). MSCs, marrow stromal cells and osteoblasts support osteoclast differentiation within the bone (Takahashi et al. 1988, Udagawa et al. 1989, Mbalaviele et al. 1999). Two main factors that are produced by MSCs and their progeny are involved in this phenomenon: macrophage colony stimulating factor (M-CSF), which induces proliferation and differentiation of pre-osteoclast cells, and receptor activator of NF-kB ligand (RANKL) that is involved in fusion and activation of these cells (Boyle et al. 2003). A recent paper published by one of us in Endocrine-Related Cancer demonstrated that human MSCs express EGFR and its ligands transforming growth factor alpha (TGF
) and amphiregulin (Normanno et al. 2005b). More importantly, this paper has shown for the first time that treatment of human MSCs with gefitinib produced a significant reduction in the synthesis of RANKL and M-CSF, and affected their ability to induce differentiation of osteoclast precursors. Angelucci et al. (2006) who found that treatment with gefitinib significantly reduced the ability of conditioned medium from prostate cancer cells to induce expression of RANKL in osteoblasts, have confirmed this observation. It is now well established that EGFR and several of its ligands are expressed by prostate cancer cell lines and human primary prostatic carcinomas (Leverton & Gullick 2000).
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An additional important question to address is whether these preclinical findings might translate into a clinical benefit for patients. Recent literature is unfortunately littered with pre-clinical hypotheses that have not been confirmed when translated into clinical trials. However, some clinical data are already available that might reveal an activity of EGFR-TKIs on bone metastases. For example, Albain et al. (2002) enrolled 12 patients with bone metastases and bone pain in a Phase II study of gefitinib in breast cancer. Surprisingly, 5/12 patients had significant relief of bone pain, leading to the complete withdrawal of all scheduled narcotics in several cases. Due to the impressive effects on bone pain palliation, two patients were maintained on gefitinib despite objective progression of the disease. A significant improvement in bone pain has also been reported in a patient enrolled in a different trial of gefitinib in metastatic breast cancer (von Minckwitz et al. 2003). Finally, activity of gefitinib on the progression of bone metastases has been recently described in non-small cell carcinoma patients (D Garfield and G Zampa, unpublished observations).
To summarize these findings, the activity of anti-EGFR agents on bone metastases appears to be related to a number of different mechanisms (Fig. 1
): (1) a direct activity on tumour cells in which anti-EGFR agents produce growth inhibition, apoptosis, and reduced invasive capacity through inhibition of molecules associated with tissue invasion such as uPA and MMP-9; (2) an anti-angiogenic activity, either direct, by affecting the proliferation and survival of endothelial cells, or indirect, by blocking the production of VEGF in MSC and in tumour cells; (3) an inhibition of osteoclast recruitment in bone lesions, by affecting the ability of bone marrow stromal cells to induce osteoclast differentiation and activation. All together, these findings highlight the importance of the activity of anti-EGFR agents on non-cancer cell types of the neoplastic microenvironment that might be involved in tumour growth and progression, such as endothelial cells and bone marrow stromal cells. Finally, the evidence summarized in this report strongly supports prospective clinical trials of anti-EGFR agents in cancer patients with bone metastases that will clarify the role of these drugs in the management of bone disease.
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Acknowledgements |
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References |
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TopAbstractReferences |
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Angelucci A, Gravina GL, Rucci N, Millimaggi D, Festuccia C, Muzi P, Teti A, Vicentini C & Bologna M 2006 Suppression of EGF-R signalling reduces the incidence of prostate cancer metastasis in nude mice. Endocrine-Related Cancer 13 197–210.
Boyle WJ, Simonet WS & Lacey DL 2003 Osteoclast differentiation and activation. Nature 423 337–342.[CrossRef][Medline]
Chan SK, Gullick WJ & Hill ME 2006 Mutations of the epidermal growth factor receptor in non-small cell lung cancer – Search and destroy. European Journal of Cancer 42 17–23.
Clark BR & Keating A 1995 Biology of bone marrow stroma. Annals of the New York Academy of Sciences 770 70–78.[Abstract]
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Guise TA & Mundy GR 1998 Cancer and bone. Endocrine Reviews 19 18–54.
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Huang SM, Li J & Harari PM 2002 Molecular inhibition of angiogenesis and metastatic potential in human squamous cell carcinomas after epidermal growth factor receptor blockade. Molecular Cancer Therapeutics 1 507–514.
Kim SJ, Uehara H, Karashima T, Shepherd DL, Killion JJ & Fidler IJ 2003 Blockade of epidermal growth factor receptor signaling in tumour cells and tumour-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice. Clinical Cancer Research 9 1200–1210.
Leverton KE & Gullick WJ 2000 The type 1 family of growth factor receptors and their ligands in prostate cancer. In ‘Endocrine Oncology’ (ed S Ethier) Humana Press Inc, New Jersey, USA, 277–291.
Mbalaviele G, Jaiswal N, Meng A, Cheng L, Van De Bos C & Thiede M 1999 Human mesenchymal stem cells promote human osteoclast differentiation from CD34+ bone marrow hematopoietic progenitors. Endocrinology 140 3736–3743.
von Minckwitz G, Jonat W, Beckmann M, De Bois A, Kleeberg U, Kuhnie H, Kettner E, Hilfrich J, Torode J & Schneeweiss A 2003 A multicenter phase II trial to evaluate Gefitinib (‘Iressa’, ZD1839) (500 mg/day) in patient with metastatic breast cancer after previous chemotherapy treatment. European Journal of Cancer Supplements 1 S133.
Nemeth JA, Yousif R, Herzog M, Che M, Upadhyay J, Shekarriz B, Bhagat S, Mullins C, Fridman R & Cher ML 2002 Matrix metalloproteinase activity, bone matrix turnover, and tumour cell proliferation in prostate cancer bone metastasis. Journal of the National Cancer Institute 94 17–25.
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Normanno N, Bianco C, De Luca A, Maiello MR & Salomon DS 2003 Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocrine-Related Cancer 10 1–22.[Abstract]
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Normanno N, De Luca A, Aldinucci D, Maiello MR, Mancino M, D’Antonio A, De Filippi R & Pinto A 2005b Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis. Endocrine-Related Cancer 12 471–482.
Roodman GD 2001 Biology of osteoclast activation in cancer. Journal of Clinical Oncology 19 3562–3571.
Salomon DS, Brandt R, Ciardiello F & Normanno N 1995 Epidermal growth factor-related peptides and their receptors in human malignancies. Critical Reviews in Oncology and Hematology 19 183–232.[ISI][Medline]
Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley JM, Martin TJ & Suda T 1988 Osteoblastic cells are involved in osteoclast formation. Endocrinology 123 2600–2602.[Abstract]
Udagawa N, Takahashi N, Akatsu T, Sasaki T, Yamaguchi A, Kodama H, Martin TJ & Suda T 1989 The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology 125 1805–1813.[Abstract]
Weber KL, Doucet M, Price JE, Baker C, Kim SJ & Fidler IJ 2003 Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice. Cancer Research 63 2940–2947.
Younes MN, Yigitbasi OG, Park YW, Kim SJ, Jasser SA, Hawthorne VS, Yazici YD, Mandal M, Bekele BN, Bucana CD, Fidler IJ & Myers JN 2005 Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation. Cancer Research 65 4716–4727.
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