© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 11, 785-787,
June 5, 2002
© 2002 Oxford University Press
EDITORIAL |
Prevention and Treatment of Lymphatic Metastasis by Antilymphangiogenic Therapy
Affiliation of authors: E. L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Correspondence to: R. K. Jain, Ph.D., E. L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, 100 Blossom Street, Boston, MA 02114 (e-mail: jain{at}steele.mgh.harvard.edu).
Cancer cells escape a tumor by two primary routes—blood vessels and lymphatic vessels—to establish distant metastases. Thus, it seems reasonable to hypothesize that blocking the growth of new blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) will inhibit hematogenic and lymphogenic metastases, respectively. An impressive array of preclinical studies has demonstrated prevention and suppression of hematogenic metastases by antiangiogenic and antivascular approaches. Whether antilymphangiogenic and antilymphatic approaches will yield similar results for lymphogenic metastases remains to be seen. Both vascular endothelial growth factor (VEGF)-C and VEGF-D induce angiogenesis (1,2) and lymphangiogenesis (1,3–5) in tumors and are associated with lymphogenic metastasis in a variety of human tumors (6). Last year Stacker et al. (1) presented the first direct evidence for the prevention of lymphatic metastasis from a tumor grown in the mammary fat pad by blocking VEGF-D. In this issue of the Journal, He et al. (7) report similar findings in subcutaneously grown tumors that lack VEGF-D by blocking VEGF-C. Although Stacker et al. (1) used a blocking antibody against VEGF-D, He et al. (7) used a receptor-antibody fusion protein (VEGFR-3-Ig fusion protein) that can trap both VEGF-C and VEGF-D. The receptor-antibody was generated in vivo by cancer cells engineered to secrete soluble VEGFR-3-Ig or by the liver infected by an adenovirus expressing VEGFR-3-Ig. In both studies, treatment was initiated within a day after tumor implantation, before the primary tumor became established, and lymph nodes were examined for metastatic lesions 4–6 weeks later. Blocking VEGF-C or VEGF-D suppressed lymphangiogenesis associated with the primary tumor and regional lymph node metastasis. These are exciting and timely findings that raise many important questions about the biology and potential treatment of lymphatic metastases.
First, how do VEGF-C and VEGF-D alter tumor biology to promote lymphatic metastasis? The current study used an ectopic (subcutaneous) model of lung cancer and found an association between lymphatic vessel density (measured as lymphatic vessel endothelial hyaluronan receptor [LYVE]-1-positive structures) and lymph node metastases in one of two tumor lines. Another recent study (4) used orthotopically grown tumors engineered to overexpress VEGF-C and found an increased diameter of functional lymphatic vessels in the tumor margin and a greater number of lymph node metastases compared with mock-transduced controls. Thus, by increasing the surface area of lymphatic vessels, VEGF-C and VEGF-D increase the opportunity for metastatic spread through lymphatic vessels. VEGF-C and VEGF-D may also serve as a survival factor for endothelial cells of newly formed or co-opted lymphatic vessels in a tumor (5). Furthermore, He et al. (7) show that trapping VEGF-C only inhibits lymphatic metastasis without affecting hematogenic lung metastasis. Some investigators have recently proposed that lung metastases from VEGF-C-overexpressing breast tumors could be secondary to lymph node metastases (8). This study does not support this hypothesis. The differential regulation of lymphogenic versus hematogenic metastases by VEGF-C and VEGF-D may be a function of the proteolytic processing of these molecules (5), which in turn may be governed by host–tumor interactions (6).
Second, what is the clinical evidence to support the use of lymphatic markers to predict lymphatic metastasis? Both VEGF-C and VEGF-D are associated with increased lymphatic metastasis in some human tumors (6). However, there is a lack of correlation between lymphatic metastasis and the density of a variety of lymphatic markers for a number of human malignancies (Table 1
), including human lung cancer, which is the subject of this preclinical study by He et al. (7). Many animal studies including this one, show a positive association between the density of lymphatic markers and lymphatic metastasis (1,3,4,7,8). Is this discordance between preclinical and clinical findings a result of the limitations of the animal models used or of the nonspecificity of current lymphatic markers? Is it possible that the markers available at present are unable to distinguish between functional and nonfunctional lymphatic vessels (Fig. 1) (4), leading to these contradictory results? Lymphatic metastasis can occur in tumors that lack intratumor functional lymphatics, suggesting that functional lymphatics in the tumor margin are responsible for lymphatic dissemination (4). Therefore, microlymphangiography in patients coupled with lymphatic identification by molecular markers is needed to provide clearer insight into lymphatic metastasis in humans.
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Third, how can antilymphangiogenic therapy be translated to the clinic? The work presented by He et al. (7), and that of Stacker et al. (1), clearly shows that lymphatic metastasis can be prevented by anti-VEGF-C and anti-VEGF-D therapy given before the establishment of the primary tumor. However, by the time most tumors are detected clinically, they are already established, and metastatic cells may have already spread to the nearby lymph nodes or distant organs. Therefore, preclinical studies that initiate treatment after the primary tumor is established and lymphatic spread has occurred are now needed to build the basis for clinical trials of antilymphangiogenic therapy. Moreover, additional molecular players other than VEGF-C and VEGF-D may be involved in determining the clinical end points. After all, metastasis is a multistep process (29) in which cancer cells must detach from their neighbors, invade the surrounding extracellular matrix, enter the blood/lymphatic vessels, survive in the lumen, attach at a distant site, extravasate, migrate, proliferate, and recruit new vessels. It is likely that VEGF-C and VEGF-D are key players for some tumors and not for others. As the techniques for detection of various proteolytically processed forms of VEGF-C and VEGF-D become widely available, we may be able to preselect tumors that are VEGF-C or VEGF-D dependent and to design appropriate interventions. The future of cancer treatment may involve a combination of agents that block the different steps of metastasis and that are tailored to individual patients on the basis of their proteomic profile. The work by He et al. (7) is an important step in this direction.
REFERENCES
1 Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7:186–91.[CrossRef][Web of Science][Medline]
2
Kadambi A, Carreira CM, Yun CO, Padera TP, Dolmans DE, Carmeliet P, et al. Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A. Cancer Res 2001;61:2404–8.
3 Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 2001;20:672–82.[CrossRef][Web of Science][Medline]
4 Padera TP, Kadambi A, Di Tomaso E, Mouta Carreira C, Brown EB, Boucher Y, et al. Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics. Science April 25, 2002; 10.1126/science.1071420.
5 Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 2002;1:219–27.[CrossRef][Web of Science][Medline]
6
Jain RK, Fenton BT. Intratumoral lymphatic vessels: a case of mistaken identity or malfunction? J Natl Cancer Inst 2002;94:417–21.
7
He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor-3 signaling. J Natl Cancer Inst 2002;94:819–25.
8 Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001;7:192–8.[CrossRef][Web of Science][Medline]
9 Jacquemier J, Mathoulin-Portier MP, Valtola R, Charafe-Jauffret E, Geneix J, Houvenaeghel G, et al. Prognosis of breast-carcinoma lymphagenesis evaluated by immunohistochemical investigation of vascular-endothelial-growth-factor receptor 3. Int J Cancer 2000;89:69–73.[CrossRef][Web of Science][Medline]
10
Nathanson SD, Zarbo RJ, Wachna DL, Spence CA, Andrzejewski TA, Abrams J. Microvessels that predict axillary lymph node metastases in patients with breast cancer. Arch Surg 2000;135:586–94.
11
Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, et al. The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. Clin Cancer Res 2000;6:4278–86.
12 Schoppmann SF, Birner P, Studer P, Breiteneder-Geleff S. Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res 2001;21:2351–5.[Web of Science][Medline]
13
Birner P, Obermair A, Schindl M, Kowalski H, Breitenecker G, Oberhuber G. Selective immunohistochemical staining of blood and lymphatic vessels reveals independent prognostic influence of blood and lymphatic vessel invasion in early-stage cervical cancer. Clin Cancer Res 2001;7:93–7.
14 Birner P, Schindl M, Obermair A, Breitenecker G, Kowalski H, Oberhuber G. Lymphatic microvessel density as a novel prognostic factor in early-stage invasive cervical cancer. Int J Cancer 2001;95:29–33.[CrossRef][Web of Science][Medline]
15 Schoppmann SF, Schindl M, Breiteneder-Geleff S, Soleima A, Breitenecker G, Karner B, et al. Inflammatory stromal reaction correlates with lymphatic microvessel density in early-stage cervival cancer. Anticancer Res 2001;21:3419–23.[Web of Science][Medline]
16
White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res 2002;62:1669–75.
17 Yokoyama Y, Sato S, Futagami M, Fukushi Y, Sakamoto T, Umemoto M, et al. Prognostic significance of vascular endothelial growth factor and its receptors in endometrial carcinoma. Gynecol Oncol 2000;77:413–8.[CrossRef][Web of Science][Medline]
18 Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Kowalski H, et al. Lymphatic microvessel density in epithelial ovarian cancer: its impact on prognosis. Anticancer Res 2000;20:2981–5.[Web of Science][Medline]
19
Yonemura Y, Endo Y, Fujita H, Fushida S, Ninomiya I, Bandou E, et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Cancer Res 1999;5:1823–9.
20 Yonemura Y, Fushida S, Bando E, Kinoshita K, Miwa K, Endo Y, et al. Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. Eur J Cancer 2001;37:918–23.[CrossRef][Web of Science][Medline]
21
Beasley NJ, Prevo R, Banerji S, Leek RD, Moore J, van Trappen P, et al. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res 2002;62:1315–20.
22 Niki T, Iba S, Yamada T, Matsuno Y, Enholm B, Hirohashi S. Expression of vascular endothelial growth factor receptor 3 in blood and lymphatic vessels of lung adenocarcinoma. J Pathol 2001;193:450–7.[CrossRef][Web of Science][Medline]
23 Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, et al. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999;81:54–61.[CrossRef][Web of Science][Medline]
24 de Waal RM, van Altena MC, Erhard H, Weidle UH, Nooijen PT, Ruiter DJ. Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination. Am J Pathol 1997;150:1951–7.[Abstract]
25 Moriyama M, Kumagai S, Kawashiri S, Kojima K, Kakihara K, Yamamoto E. Immunohistochemical study of tumour angiogenesis in oral squamous cell carcinoma. Oral Oncol 1997;33:369–74.[Web of Science][Medline]
26 Nakayama A, Ogawa A, Fukuta Y, Kudo K. Relation between lymphatic vessel diameter and clinicopathologic parameters in squamous cell carcinomas of the oral region. Cancer 1999;86:200–6.[CrossRef][Web of Science][Medline]
27
Bunone G, Vigneri P, Mariani L, Buto S, Collini P, Pilotti S, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol 1999;155:1967–76.
28
Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res 2000;60:4324–7.
29 Fidler IJ. Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis. Surg Oncol Clin N Am 2001;10:257–69.[Medline]
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