© 2000 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 28, 10-14,
2000
© 2000 Oxford University Press
Regulation of Neoplastic Angiogenesis
Presented at the Third National AIDS Malignancy Conference.
Correspondence to: Isaiah J. Fidler, D.V.M., Ph.D., Department of Cancer Biology, Box 173, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: ifidler{at}notes.mdacc.tmc.edu).
 |
ABSTRACT |
|---|
 TopNotes Abstract Cancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
The progressive growth of neoplasms and the production of metastasis depend on the development of adequate vasculature, i.e., angiogenesis. The extent of angiogenesis is determined by the balance between positive- and negative-regulating molecules that are released by tumor and host cells in the microenvironment. The growth of many neoplasms is associated with the absence of the endogenous inhibitor of angiogenesis, interferon beta (IFN
). A survey of multiple mouse and human tumors shows a lack of IFN associated with extensive angiogenesis. Therapy with IFN 
or either by subcutaneous injection of the protein or by introduction of viral vectors that contain the IFN gene inhibit angiogenesis and, hence, progressive tumor growth.
|
CANCER METASTASIS |
|---|
|
TopNotesAbstractCancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
The major cause of death from cancer is metastases that are resistant to conventional therapy. One major obstacle to the treatment of metastasis is the biologic heterogeneity of neoplasms (1). A second obstacle is the ability of different organ environments to modify a metastatic tumor cell's response to therapy (2,3). A better understanding of the mechanisms that regulate the process by which tumor cells invade local tissues and spread to distant organs should lead to the design of more effective therapy.
The process of cancer metastasis consists of a series of sequential steps, each of which can be rate limiting (1). After the initial transforming event, growth of neoplastic cells must be progressive. Extensive vascularization must occur if a tumor mass is to exceed 1 mm in diameter (4). The next step is local invasion of the host stroma that occurs by several mechanisms (5). Small tumor cell aggregates then detach and embolize next and some tumor cells that survive the trauma of the circulatory system arrest in the capillary beds of organs extravasate into the organ parenchyma, proliferate, and induce angiogenesis to allow expansion of the lesion (1).
The outcome of metastasis depends on the interactions of tumor cells with various host factors (1,6,7). The pattern of metastasis is not random but rather is determined by factors that are independent of vascular anatomy, rate of blood flow, and the number of tumor cells delivered to each organ (1). The search for factors that regulate metastasis began in 1889 when Paget analyzed postmortem data of women who died of cancer and noticed the high frequency of metastasis to the ovaries and the different incidence of skeletal metastases associated with different primary tumors. Paget concluded that the organ distribution of metastases is not a matter of chance and suggested that metastases develop only when the "seed" (certain tumor cells with metastatic ability) and the "soil" (colonized organs providing growth advantage to the seeds) are compatible (8). In recent years, Paget's hypothesis has received considerable experimental and clinical support (1,9–11). Site-specific metastasis has been demonstrated with many transplantable tumors and has also been documented in autochthonous human tumors in patients with peritoneovenous shunts (12,13).
A current definition of the "seed and soil" hypothesis encompasses three principles. First, neoplasms are biologically heterogeneous (1,14). Second, the process of metastasis is highly selective, favoring the survival and growth of a small subpopulation of cells that pre-exist in the heterogeneous parent neoplasm (6). Third, the outcome of metastasis depends on multiple interactions of metastatic cells (seed) with homeostatic mechanisms (soil) (2). The majority of malignant neoplasms actually usurp homeostatic mechanisms to gain growth advantage (1,6,7). Neoplastic angiogenesis is an excellent example.
|
TUMOR ANGIOGENESIS |
|---|
|
TopNotesAbstractCancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
The survival and growth of cells depend on an adequate supply of oxygen and nutrients and on the removal of toxic molecules. Oxygen can diffuse from capillaries for only 150–200 mm. When distances of cells from a blood supply exceed this, cell death follows (15). Thus, the expansion of tumor masses beyond 1 mm in diameter depends on neovascularization, i.e., angiogenesis (4,16). The formation of new vasculature consists of multiple, interdependent steps. It begins with local degradation of the basement membrane surrounding capillaries, followed by invasion of the surrounding stroma and migration of endothelial cells in the direction of the angiogenic stimulus. Proliferation of endothelial cells occurs at the leading edge of the migrating column and the endothelial cells begin to organize into three-dimensional structures to form new capillary tubes (4,17). Differences in cellular composition, vascular permeability, blood vessel stability, and growth regulation distinguish vessels in neoplasms from those in normal tissue (18).
The onset of angiogenesis involves a change in the local equilibrium between proangiogenic and antiangiogenic molecules (19). The major proangiogenic molecules include fibroblast growth factor (FGF) family members, vascular endothelial cell growth factor or vascular permeability factor (VEGF/VPF), interleukin 8 (IL-8), angiogenin, platelet-derived endothelial cell growth factor, platelet-derived growth factor, and matrix metalloproteinases (4,20,21). Many different proangiogenic or antiangiogenic molecules are present in different tissues (4,22). In normal tissues, factors that inhibit angiogenesis predominate (e.g., interferon beta [IFN ], tissue inhibitor of metalloproteinases) (4,23), whereas, in rapidly dividing tissues, factors that stimulate angiogenesis predominate. Our laboratory has investigated the role of cell density in the regulation of bFGF expression in human renal cell carcinoma cells or human endothelial cells. Dividing cells expressed higher levels of bFGF (both at messenger RNA [mRNA] and protein levels) than nondividing cells (24). In contrast, nondividing cells express higher levels of VEGF/VPF than dividing cells (25).
|
REGULATION OF ANGIOGENESIS BY THE MICROENVIRONMENT |
|---|
|
TopNotesAbstractCancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
The production of bFGF and IL-8 by tumor or host cells or the release of angiogenic molecules from the extracellular matrix induces the growth of endothelial cells and the formation of blood vessels. Data from our laboratory have demonstrated that the organ microenvironment can directly contribute to the induction and maintenance of the angiogenic factors bFGF (26,27) and IL-8 (28). For example, in patients with renal cell carcinoma, the level of bFGF in the serum or urine inversely associated with survival (29,30). Human renal cancer cells implanted into different organs of nude mice had different metastatic potentials: Those implanted into the kidney produced a high incidence of lung metastasis, whereas those implanted subcutaneously were not metastatic (26). Histopathologic examination of the tumors revealed that subcutaneous tumors had few blood vessels, whereas the tumors in the kidney had many (26). The subcutaneous (or intramuscular) tumors had a lower level of mRNA transcripts for bFGF than did continuously cultured cells, whereas tumors in the kidney of nude mice had 20-fold the levels of bFGF mRNA and protein level (26,27).
Constitutive expression of IL-8 directly associates with the metastatic potential of the human melanoma cells (28). IL-8 contributes to angiogenesis by inducing proliferation, migration, and invasion of endothelial cells (31). Several organ-derived cytokines (produced by inflammatory cells) can increase expression of IL-8 in normal and tumorigenic cells (32). IL-8 expression was increased in co-culture of melanoma cells with keratinocytes (skin), whereas it was inhibited in cells co-cultured with hepatocytes (liver). Similar results obtained with conditioned media from keratinocyte and hepatocyte cultures suggested that organ-derived factors, e.g., IL-1 and transforming growth factor-, can modulate the expression of IL-8 in human melanoma cells (32).
The influence of the microenvironment on the expression of VEGF/VPF, angiogenesis, tumor cell proliferation, and metastasis was investigated with the use of human gastric cancer cells implanted in orthotopic (stomach) and ectopic (subcutaneous) sites in nude mice. Tumors in the stomach were highly vascularized and expressed higher levels of VEGF/VPF than did subcutaneous tumors (33). Moreover, only tumors implanted in the stomach produced metastasis, suggesting that the expression of VEGF/VPF vascularization and metastasis of human gastric cancer cells are regulated by the organ microenvironment.
|
MOLECULAR DETERMINANTS OF ANGIOGENESIS IN CUTANEOUS HEMANGIOMAS |
|---|
|
TopNotesAbstractCancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
Infantile cutaneous hemangiomas represent a unique form of pathologic angiogenesis in which endothelial cell tumors grow rapidly in the first year of life (proliferative phase), followed by a slow regression during the next 5 years (involuting phase) and eventual involution or complete regression (involuted phase) by the age of 10–15 years (34). Long-term daily systemic treatment with IFN
has been shown to accelerate the involution of fatal hemangiomas (34–39). To determine whether the progression and involution of infantile cutaneous hemangiomas were associated with overexpression of proangiogenic molecules or the lack of antiangiogenic molecules, a large number of hemangioma specimens by immunohistochemistry was analyzed. The results showed that proliferating hemangiomas expressed bFGF and VEGF/VGF but not IFN (mRNA and protein) (40). A surprising finding was that the epidermis directly overlying proliferating hemangiomas was hyperplastic, whereas the epidermis overlying involuted hemangiomas or the epidermis from an unaffected site was not (40). The hyperplastic epidermis expressed bFGF, VEGF/VPF, and IL-8 but not IFN , whereas the normal epidermis expressed both positive- and negative-angiogenic molecules (40). These data raised the possibility that the proliferating hemangiomas induced hyperplasia in the surrounding normal tissues (epidermis), leading to production of bFGF and VEGF/VPF but not IFN (40), supporting the concept that neoplastic cells subvert and usurp host homeostatic mechanisms for their growth advantage (1,2).
To study the relationship between hemangiomas and the microenvironment, an in vivo model was developed for epidermal hyperplasia and angiogenesis, using UVB irradiation of mice (41). Mice exposed to 10 kJ/m2 UVB developed epidermal hyperplasia accompanied by angiogenesis and telangiectasia during the first week after irradiation, but these conditions slowly subsided over the following weeks. The first striking event after UVB irradiation was the increase in production of bFGF in the keratinocytes of the epidermis (41). The increase in bFGF preceded or at least coincided with the division of epidermal cells recognized by immunohistochemical staining with antibodies to proliferating cell nuclear antigen. Marked hyperplasia and angiogenesis followed immediately. The expression of VEGF/VPF was slightly increased by day 5. Of interest, the expression of IFN in the epithelium decreased with epidermal hyperplasia but was re-expressed as the hyperplasia and angiogenesis subsided (42).
Systemic therapy with the use of recombinant IFNs produces antiangiogenic effects in vascular tumors, including hemangioma (34–39), Kaposi's sarcoma (43–46), melanoma (47), basal cell and squamous cell carcinomas (48), and bladder carcinoma (49). These tumors have also been documented as producing the high levels of bFGF often detectable in the urine or serum of these patients (29,30,50). These findings, along with our in vivo observations, prompted us to investigate whether IFNs could modulate the expression of the angiogenic molecule bFGF. We found that IFN and IFN but not IFN 
decreased the expression of bFGF mRNA and protein in human renal cell cancer (HRCC) as well as in human bladder, prostate, colon, and breast carcinoma cells (51). The inhibitory effect of IFN and on bFGF expression was cell-density dependent and independent of the antiproliferative effects of IFNs (51,52). We also confirmed that IFN can inhibit bFGF production in an in vivo model system. Systemic administration of human IFN decreased the in vivo expression of bFGF, decreased blood vessel density, and inhibited tumor growth of a human bladder carcinoma implanted orthotopically in nude mice (53).
|
ANTIANGIOGENIC ACTIVITY OF IFN
|
|---|
|
TopNotesAbstractCancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
The IFN family consists of three major glycoproteins that exhibit species specificity: leukocyte-derived IFN
, fibroblast-derived IFN , and immune cell-produced IFN . Although IFN and IFN share a common receptor (the type I IFN receptor) and induce a similar pattern of cellular responses, certain cellular reactions can be stimulated only by IFN , probably by the phosphorylation of a receptor-associated protein that is uniquely responsive to IFN (54). In addition to their well-recognized activity as antiviral agents, IFNs regulate multiple biologic activities, such as cell growth (55,56), differentiation (57), oncogene expression (58,59), host immunity (60–62), and tumorigenicity (63–68). IFNs can also inhibit a number of steps in the angiogenic process. IFN has antiproliferative properties, especially on tumor cells (69–71), an effect that has also been demonstrated on endothelial cells in vitro. IFN can inhibit FGF-induced endothelial proliferation (72), and IFN can inhibit endothelial proliferation (73). IFN and IFN have been shown to be cytostatic to human dermal microvascular endothelial cells (74) and to human capillary endothelial cells (75).
The antiangiogenic effect of IFNs cannot be explained solely on the basis of inhibition of endothelial cell proliferation. For example, IFN / can also inhibit the endothelial cell migration step of angiogenesis (76,77). Subcutaneous injection of IFN / adjacent to a wound delayed the healing process by inhibiting the proliferation, migration, and invasion of capillary buds, fibroblasts, and epithelium (78,79). IFN / injected intratumorally or peritumorally into tumor cells resistant to the antiproliferative effects of IFN damages blood vessels, leading to ischemia and necrosis (80). Moreover, we reported that IFN / can affect the expression of several angiogenic factors, including bFGF (52,53), IL-8 (81), and collagenase type IV (82,83).
Our laboratory recently demonstrated that IFN gene therapy can eradicate tumor cells of various histologic origins and found that the sustained local production of murine IFN could inhibit the tumorigenicity and metastasis of human and murine tumor cells implanted into nude mice (84,85). All human tumor cell lines transfected with the murine IFN gene grew well in vitro, but none grew in vivo. IFN -transfected cells prevented the outgrowth of parental or control-transfected cells when injected at the same site but not when injected at distant sites, suggesting that IFN promoted a local lysis of the bystander cells (84,85). Similar results were found when human prostate cancer cells were infected with the murine IFN gene with the use of a retroviral vector. Of interest, the transduced cells did not grow in nude mice when injected into the prostate. The regression of the tumors was directly associated with infiltration by macrophages and activation of inducible nitric oxide synthase (86). All transfected and transduced cells stimulated a high level of nitric oxide in murine macrophages, which associated with the vigorous antitumor activities. Therefore, the local production of IFN can suppress tumorigenicity and metastasis, in part because of the activation of host effector mechanisms.
|
CONCLUSIONS |
|---|
|
TopNotesAbstractCancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
The angiogenesis within and surrounding neoplasms is due to an imbalance between proangiogenic molecules, e.g., bFGF, VEGF/VPF, IL-8, and antiangiogenic molecules (e.g., IFN). Tumor cells, normal host cells, and leukocytes all contribute to angiogenesis. The absence of IFN
from tumor beds is associated with robust angiogenesis. Restoring the balance between proangiogenic and antiangiogenic molecules provides an approach to the control of angiogenesis in neoplasms. Frequent systemic administrations of low-dose IFN or or the introduction of the IFN gene to the tumor bed show great therapeutic promise in several animal models. Clinical trials should determine whether this approach is useful for therapy of human neoplasms. |
NOTES |
|---|
Supported in part by Public Health Service grants CA16672 and R35-CA42107 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
|
REFERENCES |
|---|
|
TopNotesAbstractCancer MetastasisTumor AngiogenesisRegulation of Angiogenesis by...Molecular Determinants of...Antiangiogenic Activity of IFN...ConclusionsReferences |
|---|
1
Fidler IJ. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res 1990;50:6130–8.
2
Fidler IJ. Modulation of the organ microenvironment for the treatment of cancer metastasis. J Natl Cancer Inst 1995;87:1588–92.
3 Jain RK. Barriers to drug delivery in solid tumors. Sci Am 1994;271:58–65.[ISI][Medline]
4 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27–31.[CrossRef][ISI][Medline]
5 Liotta LA, Stetler-Stevenson WG. Tumor invasion and metastasis: an imbalance of positive and negative regulation. Cancer Res 1991;51(18 suppl):5054s–9s.
6
Fidler IJ, Kripke ML. Metastasis results from preexisting variant cells within a malignant tumor. Science 1977;197:893–5.
7 Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980;283:139–46.[CrossRef][Medline]
8 Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;1:571–3.
9 Fidler IJ. Experimental orthotopic models of organ-specific metastasis by human neoplasms. Adv Mol Cell Biol 1994;9:191–215.
10 Price JE. Host–tumor interaction in progression of breast cancer metastasis. In Vivo 1994;8:145–54.[Medline]
11 Hart IR. `Seed and soil' revisited: mechanisms of site-specific metastasis. Cancer Metastasis Rev 1982;1:5–16.[CrossRef][Medline]
12 Tarin D, Price JE, Kettlewell MG, Souter RG, Vass AC, Crossley B. Clinicopathological observations on metastasis in man studied in patients treated with peritoneovenous shunts. Br Med J (Clin Res Ed) 1984;288:749–51.
13
Tarin D, Price JE, Kettlewell MG, Souter RG, Vass AC, Crossley B. Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Res 1984;44:3584–92.
14
Fidler IJ, Hart IR. Biological diversity in metastatic neoplasms: origin and implications. Science 1982;217:998–1003.
15 Gimbrone MA Jr, Cotran RS, Leapman SB, Folkman J. Tumor growth and neovascularization: an experimental model using rabbit cornea. J Natl Cancer Inst 1974;52:413–27.
16
Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial award lecture. Cancer Res 1986;46:467–73.
17 Auerbach W, Auerbach R. Angiogenesis inhibition: a review. Pharmacol Ther 1994;63:265–311.[CrossRef][ISI][Medline]
18 Obermair A, Czerwenka K, Kurz C, Kaider A, Sevelda P. [Tumoral vascular density in breast tumors and their effect on recurrence-free survival]. Chirurg 1994;65:611–5. German.[ISI][Medline]
19 Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–64.[CrossRef][ISI][Medline]
20
Folkman J, Klagsbrun M. Angiogenic factors. Science 1987;235:442–7.
21 Bouck N, Stellmach V, Hsu SC. How tumors become angiogenic. Adv Cancer Res 1996;69:135–74.[ISI][Medline]
22 Fidler IJ, Ellis LM. The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell 1994;79:185–8.[CrossRef][ISI][Medline]
23
Folkman J. Seminars in Medicine of the Beth Israel Hospital, Boston. Clinical applications of research on angiogenesis. N Engl J Med 1995;333:1757–63.
24 Singh RK, Llansa N, Bucana CD, Sanchez R, Koura A, Fidler IJ. Cell density-dependent regulation of basic fibroblast growth factor expression in human renal cell carcinoma cells. Cell Growth Differ 1996;7:397–404.[Abstract]
25
Koura AN, Liu W, Kitadai Y, Radinsky RK, Ellis LM. Regulation of vascular endothelial growth factor expression in human colon carcinoma cells by cell density. Cancer Res 1996;56:3891–4.
26 Singh RK, Bucana CD, Gutman M, Fan D, Wilson MR, Fidler IJ. Organ site-dependent expression of basic fibroblast growth factor in human renal cell carcinoma cells. Am J Pathol 1994;145:365–74.[Abstract]
27
Singh RK, Gutman M, Bucana CD, Sanchez R, Llansa N, Fidler IJ. Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci U S A 1995;92:4562–6.
28
Singh RK, Gutman M, Radinsky R, Bucana CD, Fidler IJ. Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 1994;54:3242–7.
29
Nanus DM, Schmitz-Drager BJ, Motzer RJ, Lee AC, Vlamis V, Cordon-Cardo C, et al. Expression of basic fibroblast growth factor in primary human renal tumors: correlation with poor survival. J Natl Cancer Inst 1993;85:1597–9.
30
Nguyen M, Watanabe H, Budson AE, Richie JP, Hayes DF, Folkman J. Elevated levels of an angiogenic peptide, basic fibroblast growth factor, in the urine of patients with a wide spectrum of cancers. J Natl Cancer Inst 1994;86:356–61.
31 Leek RD, Harris AL, Lewis CE. Cytokine networks in solid human tumors: regulation of angiogenesis. J Leukoc Biol 1994;56:423–35.[Abstract]
32
Gutman M, Singh RK, Xie K, Bucana CD, Fidler IJ. Regulation of interleukin-8 expression in human melanoma cells by the organ environment. Cancer Res 1995;55:2470–5.
33 Takahashi Y, Mai M, Wilson MR, Kitadai Y, Bucana CD, Ellis LM. Site-dependent expression of vascular endothelial growth factor, angiogenesis, and proliferation in human gastric carcinoma. Int J Oncol 1996;8:701–5.
34 Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med 1992;326:1456–63.[Abstract]
35 White CW, Sondheimer HM, Crouch EC, Wilson H, Fan LL. Treatment of pulmonary hemangiomatosis with recombinant interferon-alfa-2a. N Engl J Med 1989;320:1197–200.[ISI][Medline]
36 Orchard PJ, Smith CM 3d, Woods WG, Day DL, Dehner LP, Shapiro R. Treatment of haemangioendotheliomas with alpha interferon. Lancet 1989;2:565–7.[ISI][Medline]
37 Ezekowitz A, Mulliken J, Folkman J. Interferon alpha therapy of haemangiomas in newborns and infants. Br J Haematol 1991;79(suppl 1):67–8.
38
Ricketts RR, Hatley RM, Corden BJ, Sabio H, Howell CG. Interferon--2a for the treatment of complex hemangiomas of infancy and childhood. Ann Surg 1994;219:605–14.[ISI][Medline]
39 Ohlms LA, Jones DT, McGill TJ, Healy GB. Interferon-alfa-2A therapy for airway hemangiomas. Ann Otol Rhinol Laryngol 1994;103:1–8.[ISI][Medline]
40
Bielenberg DR, Bucana CD, Sanchez R, Mulliken JB, Folkman J, Fidler IJ. Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of endogenous angiogenesis inhibitor, IFN-. Int J Oncol 1999;14:401–8.[ISI][Medline]
41
Bielenberg DR, McCarty MF, Bucana CD, Yuspa SH, Morgan D, Arbeit JM, et al. Expression of interferon- is associated with growth arrest of murine and human epidermal cells. J Invest Dermatol 1999;112:802–9.[CrossRef][ISI][Medline]
42 Bielenberg DR, Bucana CD, Sanchez R, Donawho CK, Kripke ML, Fidler IJ. Molecular regulation of UVB-induced cutaneous angiogenesis. J Invest Dermatol 1998;111:864–72.[CrossRef][ISI][Medline]
43 Groopman JE, Gottlieb MS, Goodman J, Mitsuyasu RT, Conant MA, Prince H, et al. Recombinant alpha-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome. Ann Intern Med 1984;100:671–6.
44
Real FX, Oettgen HF, Krown SE. Kaposi's sarcoma and the acquired immunodeficiency syndrome: treatment with high and low doses of recombinant leukocyte A interferon. J Clin Oncol 1986;4:544–51.
45 Rios A, Mansell PW, Newell GR, Reuben JM, Hersh EM, Gutterman JU. Treatment of acquired immunodeficiency syndrome-related Kaposi's sarcoma with lymphoblastoid interferon. J Clin Oncol 1985;3:506–12.[Abstract]
46 Mitsuyasu RT. Interferon alpha in the treatment of AIDS-related Kaposi's sarcoma. Br J Haematol 1991;79(suppl 1):69–73.
47 Legha SS. The role of interferon alfa in the treatment of metastatic melanoma. Semin Oncol 1997;24(1 suppl 4):S24–31.[ISI][Medline]
48 Tucker SB. Interferon-alpha treatment of basal cell and squamous cell skin tumors. Cancer Bull 1993;45:270–4.
49 Stadler WM, Kuzel TM, Raghavan D, Levine E, Vogelzang NJ, Roth B, et al. Metastatic bladder cancer: advances in treatment. Eur J Cancer 1997;33(suppl 1):S23–6.
50 O'Brien TS, Smith K, Cranston D, Fuggle S, Bicknell R, Harris AL. Urinary basic fibroblast growth factor in patients with bladder cancer and benign prostatic hypertrophy. Br J Urol 1995;76:311–4.[CrossRef][ISI][Medline]
51 Singh RK, Gutman M, Bucana CD, Sanchez R, Llansa N, Fidler IJ. Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. Proc Natl Acad Sci U S A 1995;92:4562–6.
52
Singh RK, Bucana CD, Llansa N, Sanchez R, Fidler IJ. Cell density-dependent modulation of basic fibroblast growth factor expression by human interferon-. Int J Oncol 1996;8:649–56.
53
Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, et al. Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res 1998;58:808–14.
54
Uze G, Lutfalla G, Morgensen KE. and interferons and their receptor and their friends and relations. J Interferon Cytokine Res 1995;15:3–26.[ISI][Medline]
55 Yaar M, Karassik RL, Schnipper LE, Gilchrest BA. Effects of alpha and beta interferons on cultured human keratinocytes. J Invest Dermatol 1985;85:70–4.[CrossRef][ISI][Medline]
56
Tamm I, Lin SL, Pfeffer LM, Sehgal PB. Interferons and as cellular regulatory molecules. In: Gresser I, editor. Interferon 9. London (U.K.): Academic Press; 1987. p. 13–74.
57 Rossi G. Interferons and cell differentiation. In: Gresser I, editor. Interferon 6. London (U.K.): Academic Press; 1985. p. 31–68.
58
Chatterjee D, Savarese TM. Posttranscriptional regulation of c-myc proto-oncogene expression and growth inhibition by recombinant human interferon- ser17 in a human colon carcinoma cell line. Cancer Chemother Pharmacol 1992;30:12–20.[CrossRef][ISI][Medline]
59
Resnitzky D, Yarden A, Zipori D, Kimchi A. Autocrine -related interferon controls c-myc suppression and growth arrest during hematopoietic cell differentiation. Cell 1986;46:31–40.[CrossRef][ISI][Medline]
60 de Maeyer-Guignard J, de Maeyer E. Immunomodulation by interferons: recent developments. In: Gresser I, editor. Interferon 6. London (U.K.): Academic Press; 1985. p. 69–91.
61 Strander H. Interferon treatment of human neoplasia. Adv Cancer Res 1986;46:1–265.[Medline]
62
Gresser I, Carnaud C, Maury C, Sala A, Eid P, Woodrow D, et al. Host humoral and cellular immune mechanisms in the continued suppression of Friend erythroleukemia metastasis after interferon / treatment in mice. J Exp Med 1991;173:1193–203.
63 Gresser I. Antitumor effects of interferon. Acta Oncol 1989;28:347–53.[ISI][Medline]
64
Ferrantini M, Proietti E, Santodonato L, Gabriele L, Peretti M, Plavec I, et al. Alpha 1-interferon gene transfer into metastatic Friend leukemia cells abrogated tumorigenicity in immunocompetent mice: antitumor therapy by means of interferon-producing cells. Cancer Res 1993;53:1107–12.
65
Gresser I, Belardelli F, Maury C, Maunoury MT, Tovey MG. Injection of mice with antibody to interferon enhances the growth of transplantable murine tumors. J Exp Med 1983;158:2095–107.
66
Gutterman JU. Cytokine therapeutics: lessons from interferon . Proc Natl Acad Sci U S A 1994;91:1198–205.
67 Gresser I. How does interferon inhibit tumor growth? In: Gresser I, editor. Interferon 6. London (U.K.): Academic Press; 1985. p. 93–126.
68 Fleischmann WR, Fleischmann CM. Mechanisms of interferons antitumor actions. In: Baron S, Coppenhaver DH, Dianzani F, Fleischmann WR Jr, Hughes TK Jr, Klimpel GR, et al., editors. Interferon: principles and medical applications. Galveston (TX): University of Texas Press; 1992. p. 299–309.
69
Gorlach A, Herter P, Hentschel H, Frosh PJ, Acker H. Effects of nIFN and rIFN on growth and morphology of two human melanoma cell lines: comparison between two- and three-dimensional cultures. Int J Cancer 1994;56:249–54.[ISI][Medline]
70
Johns TG, Mackay IR, Callister KA, Hertzog PJ, Devenish RJ, Linnane AW. Antiproliferative potencies of interferons on melanoma cell lines and xenografts: higher efficacy of interferon beta. J Natl Cancer Inst 1992;84:1185–90.
71 Sica G, Fabbroni L, Castagnetta L, Cacciatore M, Pavone-Macaluso M. Antiproliferative effect of interferons on human prostate carcinoma cell lines. Urol Res 1989;17:111–5.[ISI][Medline]
72 Heyns AP, Eldor A, Vlodavsky I, Kaiser N, Fridman R, Panet A. The antiproliferative effect of interferon and the mitogenic activity of growth factors are independent cell cycle events. Studies with vascular smooth muscle cells and endothelial cells. Exp Cell Res 1985;161:297–306.[CrossRef][ISI][Medline]
73
Friesel R, Komoriya A, Maciag T. Inhibition of endothelial cell proliferation by gamma-interferon. J Cell Biol 1987;104:689–96.
74 Ruszczak Z, Detmar M, Imcke E, Orfanos CE. Effects of rIFN-alpha, beta, and gamma on the morphology, proliferation, and cell surface antigen expression of human dermal microvascular endothelial cells in vitro. J Invest Dermatol 1990;95:693–9.[CrossRef][ISI][Medline]
75 Hicks C, Breit SN, Penny R. Response of microvascular endothelial cells to biological response modifiers. Immunol Cell Biol 1989;67:271–7.
76
Brouty-Boye D, Zetter BR. Inhibition of cell motility by interferon. Science 1980;208:516–8.
77
Fukuzawa K, Horikoshi T. Inhibitory effect of human fibroblast interferon (HuIFN-) on the growth and invasive potential of cultured human melanoma cells in vitro. Br J Dermatol 1992;126:324–30.[CrossRef][ISI][Medline]
78
Stout AJ, Gresser I, Thompson WD. Inhibition of wound healing in mice by local interferon / injection. Int J Exp Pathol 1993;74:79–85.[ISI][Medline]
79
Dvorak HF, Gresser I. Microvascular injury in pathogenesis of interferon-induced necrosis of subcutaneous tumors in mice. J Natl Cancer Inst 1989;81:497–502.
80
Sidky YA, Borden EC. Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses. Cancer Res 1987;47:5155–61.
81
Singh RK, Gutman M, Llansa N, Fidler IJ. Interferon- prevents the upregulation of interleukin-8 expression in human melanoma cells. J Interferon Cytokine Res 1996;16:577–84.[ISI][Medline]
82 Fabra A, Nakajima M, Bucana CD, Fidler IJ. Modulation of the invasive phenotype of human colon carcinoma cells by organ-specific fibroblasts of nude mice. Differentiation 1997;52:101–10.
83 Gohji K, Nakajima M, Fabra A, Bucana CD, von Eschenbach AC, Tsuruo T, et al. Regulation of gelatinase production in metastatic renal cell carcinoma by organ-specific fibroblasts. Jpn J Cancer Res 1994;85:152–60.[CrossRef][ISI][Medline]
84 Xie K, Bielenberg D, Huang S, Xu L, Salas T, Juang S, et al. Abrogation of tumorigenicity and metastasis of murine and human tumor cells by transfection with the murine IFN-beta gene: possible role of nitric oxide. Clin Cancer Res 1997;3:2283–94.[Abstract]
85 Xu L, Xie K, Fidler IJ. Therapy of human ovarian cancer by transfection with the murine interferon beta gene: role of macrophage-inducible nitric oxide synthase. Hum Gene Ther 1998;9:2699–708.[ISI][Medline]
86
Dong Z, Greene G, Pettaway C, Dinney CP, Eue I, Lu W, et al. Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-. Cancer Res 1999;59:872–9.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||