Skip to main content

Highlights on endoglin (CD105): from basic findings towards clinical applications in human cancer

Abstract

Antibody targeting of tumor-associated vasculature is a promising therapeutic approach in human cancer; however, a specific cell membrane marker for endothelial cells of tumor vasculature has not been discovered yet. Endoglin (CD105) is a cell-surface glycoprotein most recently identified as an optimal indicator of proliferation of human endothelial cells. The finding that CD105 is over-expressed on vascular endothelium in angiogenetic tissues has prompted several pre-clinical studies designed to get a deeper understanding on the role of CD105 in angiogenesis, and to evaluate the most appropriate clinical setting(s) to utilize CD105 as a therapeutic target. In this review, the foreseeable clinical applications of CD105 in human cancer are discussed.

Background

The availability of new and more sophisticated technologies, together with the improved knowledge on tumor-host interactions, have allowed the identification and characterization of different tumor-associated antigens (TAA) to be used as molecular targets for immunotherapeutic approaches in patients with solid or hematologic malignancies. Prompted by encouraging pre-clinical evidences, significant clinical results in cancer treatment have been obtained through antibody-based therapeutic regimens, such as those that target CD20 on malignant B cells [1] or HER2 in breast cancer [2]. However, due to the heterogeneous expression of TAA in neoplastic tissues, these approaches raise some critical issues such as "patients' eligibility" to specific TAA-based treatment modalities. Moreover, the efficacy of TAA targeting is frequently limited by the inadequate accessibility of therapeutic antibodies or their derived molecules within the tumor mass [3].

Currently, great interest is focused on angiogenesis and on its potential clinical implications in cancer, and vascular targeting represents a highly promising alternative to the direct engagement of therapeutic TAA on neoplastic cells [4, 5]. Among potential therapeutic strategies to induce tumor regression by blocking tumor blood supply, an intriguing approach relies on the selective targeting of cell surface molecules over-expressed on endothelial cells of tumor-associated blood vessels [4, 5]. In this setting, emerging in vitro and in vivo pre-clinical evidence identifies CD105 as a cell membrane glycoprotein representing a prime vascular target to implement innovative antibody-based diagnostic and therapeutic strategies shared by human neoplasia of different histotype.

Biological features of CD105

Tissue distribution

CD105 is a 180 kDa transmembrane glycoprotein constitutively phosphorylated [6–10], with a marked tissue-specificity [11]. Supporting this notion, CD105 is predominantly expressed on endothelial cells [11–13] and its promoter is strongly and selectively active in endothelial cells [14, 15]. Consistently, elevated levels of CD105 expression were detected on human microvascular endothelium [16] and on vascular endothelial cells in tissues undergoing active angiogenesis, such as regenerating and inflamed tissues or tumors [11, 12, 17–21]. However, CD105 was also weakly expressed on selected non-endothelial cells of different histotype (Table 1 and ref [22, 23] for review).

Table 1 In vivo distribution of CD105 on non-endothelial cells.

In solid neoplasia, CD105 is present on endothelial cells of both peri- and intra-tumoral blood vessels and on tumor stromal components [11, 17, 22–24]. In particular, CD105 is largely expressed in small and likely immature tumor vessels as demonstrated in breast, prostate and gastric cancer [24–26]; rarely, CD105 is expressed in the cytoplasm of neoplastic cells [23]. In lung carcinoma, staining for CD105 was reported to be strong at the areas of active angiogenesis including tumor edge, while it was less intense in the central area of the tumor and not detectable in the adjacent normal tissue [12].

Functional activity

CD105 is a component of the receptor complex of Transforming Growth Factor (TGF)-β [27–29], a pleiotropic cytokine involved in cellular proliferation, differentiation and migration [30]. It binds several components of the TGF-β superfamily [27, 29]. Interestingly, binding of TGF-β1 to CD105 reduces the levels of CD105 phosphorylation [10] and the levels of CD105 expression modulate the effects of TGF-β1 [28, 31–35]. In this respect, it is of interest that the inhibition of CD105 expression enhanced the ability of TGF-β1 to suppress growth, migration and capacity to form capillary tubes of cultured endothelial cells [32].

In the absence of TGF-β1, CD105 shows an anti-apoptotic effect in endothelial cells under hypoxic stress, suggesting for a protective role of CD105 against pro-apoptotic factors [36].

In addition, the discovery that levels of CD105 regulate the expression of different components of the extracellular matrix including fibronectin, collagen, PAI-1 and lumican [34, 37, 38], is also suggestive for a crucial role of CD105 in cellular transmigration [38].

Modulation

Different environmental factors and cytokines involved in angiogenesis modulate CD105 expression. The levels of CD105 protein, mRNA and promoter activity are up-regulated by hypoxia [39] and by TGF-β1 [28, 39–41], which cooperate to induce the expression of CD105 at transcriptional level [39]. Instead, TNF-α down-regulates CD105 protein levels but it has no effect at the transcriptional level [42].

Furthermore, CD105 expression was up-regulated on human umbilical vein endothelial cells (HUVEC) infected with a recombinant adenovirus carrying a constitutively active form of activin receptor-like kinase (ALK)-1, a type I TGF-β receptor [43].

Supporting the in vivo modulation of CD105 by pro-angiogenetic stimuli, elevated levels of CD105 were associated with high levels of vascular endothelial growth factor in non-small cell lung cancer lesions positive for angiopoietin-2, a regulatory factor of survival of endothelial cells, considerably expressed at sites of vascular remodelling and in highly vascularized tumors [44].

CD105 and vascularization

Even if its functional role is not fully understood, several findings suggest for the involvement of CD105 in angiogenesis and vascular development, and in maintaining vessel wall integrity.

First, CD105 expression is up-regulated on proliferating endothelial cells in culture [11–13] and on endothelial cells of angiogenetic blood vessels [11, 12, 24, 33, 45]. Furthermore, CD105 knockout mice died of defective vascular development during early gestation [46], as observed in TGF-β1- and ALK-1-null mice [47, 48]. In particular, CD105 null mice showed important structural defects in the primitive vascular plexus of the yolk sac that prevented the formation of normal mature vessels [46]. Additionally, both in humans and mice, CD105 gene mutations are associated with hereditary hemorrhagic telangiectasia type 1, an inherited disease characterized by arteriovenous malformations and bleedings [49–51]. Finally, CD105 has been most recently suggested as a regulator factor of nitric oxide-dependent vasodilatation. In fact, the levels of CD105 expression modulated the amounts of endothelial nitric oxide synthase (eNOS) in kidney and femoral arteries of mice. Furthermore, over-expression or suppression of CD105 in cultured endothelial cells induced a marked increase or decrease in the protein levels of eNOS, respectively [52].

Interestingly, an increment in microvessel density, as determined by immunohistochemical staining for CD105, was found during the progressive stages of colorectal carcinogenesis [53]. In line with this finding, the assessment of neovascularization by CD105 staining was found to represent a potential predictor of prognosis in different solid malignancies (Table 2 and Table 3). For instance, the CD105-positive blood vessels count was prognostic for survival in patients with prostate cancer of Gleason score 5–7 [25], and correlated with overall survival of node-negative patients affected by breast carcinoma [54, 55].

Table 2 Intra-tumor microvessel density determined by immunohistochemical staining for CD105: an indicator of poor prognosis in patients with solid neoplasia.
Table 3 CD105 as a marker of survival in patients with solid tumors of different histotype.

mAb directed to CD105 but not to the pan-endothelial marker CD34 revealed an inverse correlation between intra-tumoral microvessel density and apoptotic index of neoplastic cells in non-small cell lung cancer patients [56]. Since angiogenesis is crucial for tumor development and progression [57], this finding provided supportive evidence to the usefulness of CD105 targeting in antiangiogenetic therapy of cancer [56].

CD105 targeting

Ex vivo background

Selected anti-CD105 monoclonal antibodies (mAb) significantly inhibit the proliferation of cultured human microvascular and macrovascular endothelial cells [11, 58, 59], thus supporting the notion that CD105 is a promising vascular target to implement innovative antibody-based therapeutic strategies in human cancer. Noteworthy, differences in the growth suppression of endothelial cells have been found among 4 anti-CD105 mAb defining different epitopes [59]; nevertheless, TGF-β1 and each of the 4 anti-CD105 mAb showed synergistic suppression of HUVEC proliferation [59].

A bispecific single-chain diabody directed to the adenovirus fiber knob domain and to CD105 was shown to be effective in enhancing adenovirus transduction in HUVEC, thus sustaining the use of CD105 protein as target for therapeutic gene transfer in endothelial cells [60]. Along this line, a vector constructed with the CD105 promoter was efficiently utilized to deliver gene expression specifically to endothelial cells of mouse blood vessels [61]. Additionally, human CD105 promoter fragments were successfully utilized in pigs to drive CD59 expression in the small vessels of heart, kidney and lung, but not in the large vessels of these organs [62].

Most recently, another bispecific single-chain diabody was proposed for therapeutic approaches aiming to destroy tumor-associated vasculature. This engineered antibody is directed to human CD105 as well as CD3 and it is effective to mediate killing of CD105-positive endothelial cells by cytotoxic T lymphocytes [63]. An alternative strategy of CD105 targeting for anti-angiogenetic treatment of cancer might derive by the use of conditionally replicating adenoviruses (CRAD). In fact, CRAD obtained by utilizing Flk-1 and CD105 regulatory elements have been transcriptionally targeted towards proliferating endothelial cells, with specificity and efficacy in killing HUVEC [64].

In vivo diagnostic targeting

The over-expression of CD105 on proliferating endothelial cells of the tumour vasculature suggested that CD105 might also represent a good target for the immunoscintigraphy of tumors. In keeping with this idea, targeting of CD105 by radiolabeled mAb was described as a safe and effective procedure to image tumors in animal models [13, 65]. The intravenous administration of a 125I-labeled anti-CD105 mAb efficiently imaged spontaneous mammary adenocarcinomas in dogs. The immunoscintigraphy performed 8 hours after mAb injection demonstrated that the uptake of the radiolabeled mAb was rapid and intense, and no systemic side effects were observed in the injected dogs during a 3 months follow-up after imaging procedures [13]. Consistently, the scintigraphy performed 15 minutes after administration of low doses of 111In-labeled anti-CD105 mAb in C57BL/6 mice demonstrated an accumulation of radioactivity in xenografts of human melanoma. The autoradiography and immunohistology showed a marked concentration of the mAb in the periphery of the tumor mass with an heterogeneous distribution in its centre. Noteworthy, the 97% of the injected dose of the radiolabeled anti-CD105 mAb was removed from the circulation within 15 min, and the blood half-life of the anti-CD105 mAb was estimated to be <1 minute [65].

The immunoscintigraphy performed after renal artery perfusion of 99Tcm-labeled anti-CD105 mAb in the freshly excised kidney from a patient with renal carcinoma identified 2 distinct hot spots of radioactivity, which matched the positions of the tumors, as demonstrated by the subsequent histopathologic examination; noteworthy, only one of the two tumor masses was identified by a pre-surgery magnetic resonance imaging scan [66].

In vivo therapeutic targeting

Targeting of CD105, as therapeutic antiangiogenetic approach in cancer, has been extensively investigated in severe combined immunodeficiency [SCID] mice bearing human breast tumors. The results of these studies demonstrated a long lasting suppression of tumor growth and metastasis by systemic administration of radiolabeled or immunotoxin-conjugated anti-CD105 mAb [67–69]. Furthermore, naked anti-CD105 mAb, which reacted strongly with proliferating human endothelial cells but weakly with murine endothelial cells, showed synergism with conventional chemotherapeutic regimens in a human skin/SCID mouse chimera model [70]. Interestingly, in all these animal models the anti-tumor efficacy and the anti-metastatic activities were identified in the ability of the anti-CD105 mAb to inhibit tumor-associated angiogenesis and/or to obliterate tumor-associated vasculature [67–70].

Conclusions and future directions

A number of convincing experimental findings suggest that selected anti-CD105 mAb can strongly localize to the endothelium of tumor-associated vasculature and that they are efficient to inhibit tumor angiogenesis, tumor growth and metastasis in mice, pointing to CD105 as a suitable vascular target to implement antibody-based therapeutic approaches in cancer.

However, concern about the therapeutic applications of anti-CD105 mAb and their derived molecules in cancer patients emerged by discrepancies observed in the expression of CD105 within normal and tumor tissues [71–74]. In this respect, it has been suggested that not all anti-CD105 mAb are useful for anti-angiogenetic targeting since different mAb have different reactivity with the vasculature of normal tissues [45, 59, 66, 73]. Based on these findings, the comparative evaluation of the reactivity of a large panel of anti-CD105 mAb in the same tumor specimen has been proposed to identify the most reactive with tumor endothelium [45].

Nevertheless, the information on CD105 so far obtained by ex vivo studies and in animal models warrants additional efforts to further define the most appropriate therapeutic setting [s] for CD105 in human cancer, and to translate pre-clinical evidences into phase I/II clinical trials.

Abbreviations

ALK:

activin receptor-like kinase

CRAD:

conditionally replicating adenoviruses

eNOS:

endothelial nitric oxide synthase

HUVEC:

human umbilical vein endothelial cells

TAA:

tumor-associated antigens

TGF:

transforming growth factor

References

  1. Smith MR: Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene. 2003, 22: 7359-7368. 10.1038/sj.onc.1206939.

    Article  CAS  PubMed  Google Scholar 

  2. Ménard S, Pupa SM, Campiglio M, Tagliabue E: Biologic and therapeutic role of HER2 in cancer. Oncogene. 2003, 22: 6570-6578. 10.1038/sj.onc.1206779.

    Article  PubMed  Google Scholar 

  3. Green MC, Murray JL, Hortobagyi GN: Monoclonal antibody therapy for solid tumors. Cancer Treat Rev. 2000, 26: 269-286. 10.1053/ctrv.2000.0176.

    Article  CAS  PubMed  Google Scholar 

  4. Brekken RA, Li C, Kumar S: Strategies for vascular targeting in tumors. Int J Cancer. 2002, 100: 123-130. 10.1002/ijc.10462.

    Article  CAS  PubMed  Google Scholar 

  5. Thorpe PE: Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004, 10: 415-427.

    Article  PubMed  Google Scholar 

  6. Haruta Y, Seon BK: Distinct human leukemia-associated cell surface glycoprotein GP160 defined by monoclonal antibody SN6. Proc Natl Acad Sci U S A. 1986, 83: 7898-7902.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Gougos A, Letarte M: Identification of a human endothelial cell antigen with monoclonal antibody 44G4 produced against a pre-B leukemic cell line. J Immunol. 1988, 141: 1925-1933.

    CAS  PubMed  Google Scholar 

  8. Gougos A, Letarte M: Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem. 1990, 265: 8361-8364.

    CAS  PubMed  Google Scholar 

  9. Bellón T, Corbi A, Lastres P, Calés C, Cebrian M, Vera S, Cheifetz S, Massagué J, Letarte M, Bernabéu C: Identification and expression of two forms of the human transforming growth factor-beta-binding protein endoglin with distinct cytoplasmic regions. Eur J Immunol. 1993, 23: 2340-2345.

    Article  PubMed  Google Scholar 

  10. Lastres P, Martín-Perez J, Langa C, Bernabéu C: Phosphorylation of the human-transforming-growth-factor-β-binding protein endoglin. Biochem J. 1994, 301: 765-768.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Burrows FJ, Derbyshire EJ, Tazzari PL, Amlot P, Gazdar AF, King SW, Letarte M, Vitetta ES, Thorpe PE: Up-regulation of endoglin on vascular endothelial cells in human solid tumors: implications for diagnosis and therapy. Clin Cancer Res. 1995, 1: 1623-1634.

    CAS  PubMed  Google Scholar 

  12. Miller DW, Graulich W, Karges B, Stahl S, Ernst M, Ramaswamy A, Sedlacek HH, Müller R, Adamkiewicz J: Elevated expression of endoglin, a component of the TGF-β-receptor complex, correlates with proliferation of tumor endothelial cells. Int J Cancer. 1999, 81: 568-572. 10.1002/(SICI)1097-0215(19990517)81:4<568::AID-IJC11>3.3.CO;2-O.

    Article  CAS  PubMed  Google Scholar 

  13. Fonsatti E, Jekunen AP, Kairemo KJ, Coral S, Snellman M, Nicotra MR, Natali PG, Altomonte M, Maio M: Endoglin is a suitable target for efficient imaging of solid tumors: in vivo evidence in a canine mammary carcinoma model. Clin Cancer Res. 2000, 6: 2037-2043.

    CAS  PubMed  Google Scholar 

  14. Graulich W, Nettelbeck DM, Fischer D, Kissel T, Muller R: Cell type specificity of the human endoglin promoter. Gene. 1999, 227: 55-62. 10.1016/S0378-1119(98)00585-X.

    Article  CAS  PubMed  Google Scholar 

  15. Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S, Bernabeu C: Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood. 2002, 100: 4001-4010. 10.1182/blood.V100.12.4001.

    Article  CAS  PubMed  Google Scholar 

  16. Wong SH, Hamel L, Chevalier S, Philip A: Endoglin expression on human microvascular endothelial cells association with betaglycan and formation of higher order complexes with TGF-beta signalling receptors. Eur J Biochem. 2000, 267: 5550-5560. 10.1046/j.1432-1327.2000.01621.x.

    Article  CAS  PubMed  Google Scholar 

  17. Wang JM, Kumar S, Pye D, van Agthoven AJ, Krupinski J, Hunter RD: A monoclonal antibody detects heterogeneity in vascular endothelium of tumours and normal tissues. Int J Cancer. 1993, 54: 363-370.

    Article  CAS  PubMed  Google Scholar 

  18. Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM: Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994, 25: 1794-1798.

    Article  CAS  PubMed  Google Scholar 

  19. Schimming R, Marme D: Endoglin (CD105) expression in squamous cell carcinoma of the oral cavity. Head Neck. 2002, 24: 151-156. 10.1002/hed.10040.abs.

    Article  PubMed  Google Scholar 

  20. Torsney E, Charlton R, Parums D, Collis M, Arthur HM: Inducible expression of human endoglin during inflammation and wound healing in vivo. Inflamm Res. 2002, 51: 464-470.

    Article  CAS  PubMed  Google Scholar 

  21. Chung YC, Hou YC, Pan AC: Endoglin (CD105) expression in the development of haemorrhoids. Eur J Clin Invest. 2004, 34: 107-112. 10.1111/j.1365-2362.2004.01305.x.

    Article  CAS  PubMed  Google Scholar 

  22. Fonsatti E, Del Vecchio L, Altomonte M, Sigalotti L, Nicotra MR, Coral S, Natali PG, Maio M: Endoglin: An accessory component of the TGF-beta-binding receptor-complex with diagnostic, prognostic, and bioimmunotherapeutic potential in human malignancies. J Cell Physiol. 2001, 188: 1-7. 10.1002/jcp.1095.

    Article  CAS  PubMed  Google Scholar 

  23. Fonsatti E, Altomonte M, Nicotra MR, Natali PG, Maio M: Endoglin (CD105): a powerful therapeutic target on tumor-associated angiogenetic blood vessels. Oncogene. 2003, 22: 6557-6563. 10.1038/sj.onc.1206813.

    Article  CAS  PubMed  Google Scholar 

  24. Wang JM, Kumar S, Pye D, Haboubi N, Al-Nakib L: Breast carcinoma: comparative study of tumor vasculature using two endothelial cell markers. J Natl Cancer Inst. 1994, 86: 386-388.

    Article  CAS  PubMed  Google Scholar 

  25. Wikstrom P, Lissbrant IF, Stattin P, Egevad L, Bergh A: Endoglin [CD105] is expressed on immature blood vessels and is a marker for survival in prostate cancer. Prostate. 2002, 51: 268-275. 10.1002/pros.10083.

    Article  CAS  PubMed  Google Scholar 

  26. Yu JX, Zhang XT, Liao YQ, Zhang QY, Chen H, Lin M, Kumar S: Relationship between expression of CD105 and growth factors in malignant tumors of gastrointestinal tract and its significance. World J Gastroenterol. 2003, 9: 2866-2869.

    Article  CAS  PubMed  Google Scholar 

  27. Cheifetz S, Bellón T, Calés C, Vera S, Bernabéu C, Massagué J, Letarte M: Endoglin is a component of the transforming growth factor-β receptor system in human endothelial cells. J Biol Chem. 1992, 267: 19027-19030.

    CAS  PubMed  Google Scholar 

  28. Lastres P, Letamendía A, Zhang H, Ríus C, Almendro N, Raab U, López LA, Langa C, Fabra A, Letarte M, Bernabéu C: Endoglin modulates cellular response to TGF-β1. J Cell Biol. 1996, 133: 1109-1121. 10.1083/jcb.133.5.1109.

    Article  CAS  PubMed  Google Scholar 

  29. Barbara NP, Wrana JL, Letarte M: Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-β superfamily. J Biol Chem. 1999, 274: 584-594. 10.1074/jbc.274.2.584.

    Article  CAS  PubMed  Google Scholar 

  30. Govinden R, Bhoola KD: Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther. 2003, 98: 257-265. 10.1016/S0163-7258(03)00035-4.

    Article  CAS  PubMed  Google Scholar 

  31. Letamendía A, Lastres P, Botella LM, Raab U, Langa C, Velasco B, Attisano L, Bernabéu C: Role of endoglin in cellular responses to transforming growth factor-β. J Biol Chem. 1998, 273: 33011-33019. 10.1074/jbc.273.49.33011.

    Article  PubMed  Google Scholar 

  32. Li C, Hampson IN, Hampson L, Kumar P, Bernabéu C, Kumar S: CD105 antagonizes the inhibitory signaling of transforming growth factor β1 on human vascular endothelial cells. FASEB J. 2000, 14: 55-64.

    CAS  PubMed  Google Scholar 

  33. Ma X, Labinaz M, Goldstein J, Millere H, Keon WJ, Letarte M, O'Brien E: Endoglin is overexpressed after arterial injury and is required for transforming growth factor-β-induced inhibition of smooth muscle cell migration. Arterioscler Thromb Vasc Biol. 2000, 20: 2546-2552.

    Article  CAS  PubMed  Google Scholar 

  34. Diez-Marques L, Ortega-Velazquez R, Langa C, Rodriguez-Barbero A, Lopez-Novoa JM, Lamas S, Bernabeu C: Expression of endoglin in human mesangial cells: modulation of extracellular matrix synthesis. Biochim Biophys Acta. 2002, 1587: 36-44. 10.1016/S0925-4439(02)00051-0.

    Article  CAS  PubMed  Google Scholar 

  35. Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C: Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II. J Biol Chem. 2002, 277: 29197-29209. 10.1074/jbc.M111991200.

    Article  CAS  PubMed  Google Scholar 

  36. Li C, Issa R, Kumar P, Hampson IN, Lopez-Novoa JM, Bernabeu C, Kumar S: CD105 prevents apoptosis in hypoxic endothelial cells. J Cell Sci. 2003, 116: 2677-2685. 10.1242/jcs.00470.

    Article  CAS  PubMed  Google Scholar 

  37. Guerrero-Esteo M, Lastres P, Letamendia A, Perez-Alvarez MJ, Langa C, Lopez LA, Fabra A, Garcia-Pardo A, Vera S, Letarte M, Bernabeu C: Endoglin overexpression modulates cellular morphology, migration, and adhesion of mouse fibroblasts. Eur J Cell Biol. 1999, 78: 614-623.

    Article  CAS  PubMed  Google Scholar 

  38. Botella LM, Sanz-Rodriguez F, Sanchez-Elsner T, Langa C, Ramirez JR, Vary C, Roughley PJ, Bernabeu C: Lumican is down-regulated in cells expressing endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression. Matrix Biol. 2004, 22: 561-572. 10.1016/j.matbio.2003.11.006.

    Article  CAS  PubMed  Google Scholar 

  39. Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C: Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem. 2002, 277: 43799-43808. 10.1074/jbc.M207160200.

    Article  CAS  PubMed  Google Scholar 

  40. Ríus C, Smith JD, Almendro N, Langa C, Botella LM, Marchuk DA, Vary CPH, Bernabéu C: Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1. Blood. 1998, 92: 4677-4690.

    PubMed  Google Scholar 

  41. Zhu Y, Sun Y, Xie L, Jin K, Sheibani N, Greenberg DA: Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain microvascular endothelial cells. Stroke. 2003, 34: 2483-8. 10.1161/01.STR.0000088644.60368.ED.

    Article  CAS  PubMed  Google Scholar 

  42. Li C, Guo B, Ding S, Rius C, Langa C, Kumar P, Bernabeu C, Kumar S: TNF alpha down-regulates CD105 expression in vascular endothelial cells: a comparative study with TGF beta 1. Anticancer Res. 2003, 23: 1189-1196.

    CAS  PubMed  Google Scholar 

  43. Ota TM, Fujii M, Sugizaki T, Ishii M, Miyazawa K, Aburatani H, Miyazono K: Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells. J Cell Physiol. 2002, 193: 299-318. 10.1002/jcp.10170.

    Article  CAS  PubMed  Google Scholar 

  44. Tanaka F, Ishikawa S, Yanagihara K, Miyahara R, Kawano Y, Li M, Otake Y, Wada H: Expression of angiopoietins and its clinical significance in non-small cell lung cancer. Cancer Res. 2002, 62: 7124-7129.

    CAS  PubMed  Google Scholar 

  45. Duff SE, Li C, Garland JM, Kumar S: CD105 is important for angiogenesis: evidence and potential applications. FASEB J. 2003, 17: 984-992. 10.1096/fj.02-0634rev.

    Article  CAS  PubMed  Google Scholar 

  46. Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP: Defective angiogenesis in mice lacking endoglin. Science. 1999, 284: 1534-1537. 10.1126/science.284.5419.1534.

    Article  CAS  PubMed  Google Scholar 

  47. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ: Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development. 1995, 121: 1845-54.

    CAS  PubMed  Google Scholar 

  48. Urness LD, Sorensen LK, Li DY: Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet. 2000, 26: 328-331. 10.1038/81634.

    Article  CAS  PubMed  Google Scholar 

  49. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, McCormick MK, Pericak-Vance MA, Heutink P, Oostra BA, Haitjema T, Westerman CJJ, Porteous ME, Guttmacher AE, Letarte M, Marchuk DA: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994, 8: 345-351.

    Article  CAS  PubMed  Google Scholar 

  50. Bourdeau A, Faughnan ME, McDonald ML, Paterson AD, Wanless IR, Letarte M: Potential role of modifier genes influencing transforming growth factor-beta1 levels in the development of vascular defects in endoglin heterozygous mice with hereditary hemorrhagic telangiectasia. Am J Pathol. 2001, 158: 2011-2020.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. van den Driesche S, Mummery CL, Westermann CJ: Hereditary hemorrhagic telangiectasia: an update on transforming growth factor beta signaling in vasculogenesis and angiogenesis. Cardiovasc Res. 2003, 58: 20-31. 10.1016/S0008-6363(02)00852-0.

    Article  CAS  PubMed  Google Scholar 

  52. Jerkic M, Rivas-Elena JV, Prieto M, Carron R, Sanz-Rodriguez F, Perez-Barriocanal F, Rodriguez-Barbero A, Bernabeu C, Lopez-Novoa JM: Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J. 2004, 18: 609-611.

    CAS  PubMed  Google Scholar 

  53. Akagi K, Ikeda Y, Sumiyoshi Y, Kimura Y, Kinoshita J, Miyazaki M, Abe T: Estimation of angiogenesis with anti-CD105 immunostaining in the process of colorectal cancer development. Surgery. 2002, 131 (1 Suppl): S109-113. 10.1067/msy.2002.119361.

    Article  PubMed  Google Scholar 

  54. Dales JP, Garcia S, Carpentier S, Andrac L, Ramuz O, Lavaut MN, Allasia C, Bonnier P, Taranger-Charpin C: Long-term prognostic significance of neoangiogenesis in breast carcinomas: comparison of Tie-2/Tek, CD105, and CD31 immunocytochemical expression. Hum Pathol. 2004, 35: 176-183. 10.1016/j.humpath.2003.10.008.

    Article  CAS  PubMed  Google Scholar 

  55. Dales JP, Garcia S, Carpentier S, Andrac L, Ramuz O, Lavaut MN, Allasia C, Bonnier P, Taranger-Charpin C: Prediction of metastasis risk [11 year follow-up] using VEGF-R1, VEGF-R2, Tie-2/Tek and CD105 expression in breast cancer [n = 905]. Br J Cancer. 2004, 90: 1216-1221. 10.1038/sj.bjc.6601452.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Tanaka F, Otake Y, Yanagihara K, Kawano Y, Miyahara R, Li M, Ishikawa S, Wada H: Correlation between apoptotic index and angiogenesis in non-small cell lung cancer: comparison between CD105 and CD34 as a marker of angiogenesis. Lung Cancer. 2003, 39: 289-296. 10.1016/S0169-5002(02)00534-2.

    Article  PubMed  Google Scholar 

  57. Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature. 2000, 407: 249-257. 10.1038/35025220.

    Article  CAS  PubMed  Google Scholar 

  58. Maier JA, Delia D, Thorpe PE, Gasparini G: In vitro inhibition of endothelial cell growth by the antiangiogenic drug AGM-1470 [TNP-470] and the anti-endoglin antibody TEC-11. Anticancer Drugs. 1997, 8: 238-244.

    Article  CAS  PubMed  Google Scholar 

  59. She X, Matsuno F, Harada N, Tsai H, Seon BK: Synergy between anti-endoglin [CD105] monoclonal antibodies and TGF-beta in suppression of growth of human endothelial cells. Int J Cancer. 2004, 108: 251-257. 10.1002/ijc.11551.

    Article  CAS  PubMed  Google Scholar 

  60. Nettelbeck DM, Miller DW, Jerome V, Zuzarte M, Watkins SJ, Hawkins RE, Muller R, Kontermann RE: Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin [CD105]. Mol Ther. 2001, 3: 882-891. 10.1006/mthe.2001.0342.

    Article  CAS  PubMed  Google Scholar 

  61. Velasco B, Ramirez JR, Relloso M, Li C, Kumar S, Lopez-Bote JP, Perez-Barriocanal F, Lopez-Novoa JM, Cowan PJ, d'Apice AJ, Bernabeu C: Vascular gene transfer driven by endoglin and ICAM-2 endothelial-specific promoters. Gene Ther. 2001, 8: 897-904. 10.1038/sj.gt.3301468.

    Article  CAS  PubMed  Google Scholar 

  62. Cowan PJ, Shinkel TA, Fisicaro N, Godwin JW, Bernabeu C, Almendro N, Rius C, Lonie AJ, Nottle MB, Wigley PL, Paizis K, Pearse MJ, d'Apice AJ: Targeting gene expression to endothelium in transgenic animals: a comparison of the human ICAM-2, PECAM-1 and endoglin promoters. Xenotransplantation. 2003, 10: 223-231.

    Article  PubMed  Google Scholar 

  63. Korn T, Muller R, Kontermann RE: Bispecific single-chain diabody-mediated killing of endoglin-positive endothelial cells by cytotoxic T lymphocytes. J Immunother. 2004, 27: 99-106. 10.1097/00002371-200403000-00003.

    Article  CAS  PubMed  Google Scholar 

  64. Savontaus MJ, Sauter BV, Huang TG, Woo SL: Transcriptional targeting of conditionally replicating adenovirus to dividing endothelial cells. Gene Ther. 2002, 9: 972-979. 10.1038/sj.gt.3301747.

    Article  CAS  PubMed  Google Scholar 

  65. Bredow S, Lewin M, Hofmann B, Marecos E, Weissleder R: Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin. Eur J Cancer. 2000, 36: 675-681. 10.1016/S0959-8049(99)00335-4.

    Article  CAS  PubMed  Google Scholar 

  66. Costello B, Li C, Duff S, Butterworth D, Khan A, Perkins M, Owens S, Al-Mowallad AF, O'Dwyer S, Kumar S: Perfusion of 99Tcm-labeled CD105 Mab into kidneys from patients with renal carcinoma suggests that CD105 is a promising vascular target. Int J Cancer. 2004, 109: 436-441. 10.1002/ijc.11699.

    Article  CAS  PubMed  Google Scholar 

  67. Seon BK, Matsuno F, Haruta Y, Kondo M, Barcos M: Long-lasting complete inhibition of human solid tumors in SCID mice by targeting endothelial cells of tumor vasculature with antihuman endoglin immunotoxin. Clin Cancer Res. 1997, 3: 1031-1044.

    CAS  PubMed  Google Scholar 

  68. Matsuno F, Haruta Y, Kondo M, Tsai H, Barcos M, Seon BK: Induction of lasting complete regression of preformed distinct solid tumors by targeting the tumor vasculature using two new anti-endoglin monoclonal antibodies. Clin Cancer Res. 1999, 5: 371-382.

    CAS  PubMed  Google Scholar 

  69. Tabata M, Kondo M, Haruta Y, Seon BK: Antiangiogenic radioimmunotherapy of human solid tumors in SCID mice using 125I-labeled anti-endoglin monoclonal antibodies. Int J Cancer. 1999, 82: 737-742. 10.1002/(SICI)1097-0215(19990827)82:5<737::AID-IJC18>3.3.CO;2-#.

    Article  CAS  PubMed  Google Scholar 

  70. Takahashi N, Haba A, Matsuno F, Seon BK: Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin [CD105] monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide. Cancer Res. 2001, 61: 7846-7854.

    CAS  PubMed  Google Scholar 

  71. Griffioen AW, Damen CA, Blijham GH, Groenewegen G: Endoglin/CD105 may not be an optimal tumor endothelial treatment target. Breast Cancer Res Treat. 1996, 39: 239-242.

    Article  CAS  PubMed  Google Scholar 

  72. Balza E, Castellani P, Zijlstra A, Neri D, Zardi L, Siri A: Lack of specificity of endoglin expression for tumor blood vessels. Int J Cancer. 2001, 94: 579-585. 10.1002/ijc.1505.

    Article  CAS  PubMed  Google Scholar 

  73. Seon BK: Expression of endoglin [CD105] in tumor blood vessels. Int J Cancer. 2002, 99: 310-311. 10.1002/ijc.10378.

    Article  CAS  PubMed  Google Scholar 

  74. Grisanti S, Canbek S, Kaiserling E, Adam A, Lafaut B, Gelisken F, Szurman P, Henke-Fahle S, Oficjalska-Mlynczak J, Bartz-Schmidt KU: Expression of endoglin in choroidal neovascularization. Exp Eye Res. 2004, 78: 207-213. 10.1016/j.exer.2003.11.008.

    Article  CAS  PubMed  Google Scholar 

  75. Kumar S, Ghellal A, Li C, Byrne G, Haboubi N, Wang JM, Bundred N: Breast carcinoma: vascular density determined using CD105 antibody correlates with tumor prognosis. Cancer Res. 1999, 59: 856-861.

    CAS  PubMed  Google Scholar 

  76. Dales JP, Garcia S, Bonnier P, Duffaud F, Andrac-Meyer L, Ramuz O, Lavaut MN, Allasia C, Charpin C: CD105 expression is a marker of high metastatic risk and poor outcome in breast carcinomas. Correlations between immunohistochemical analysis and long-term follow-up in a series of 929 patients. Am J Clin Pathol. 2003, 119: 374-380.

    Article  PubMed  Google Scholar 

  77. Brewer CA, Setterdahl JJ, Li MJ, Johnston JM, Mann JL, McAsey ME: Endoglin expression as a measure of microvessel density in cervical cancer. Obstet Gynecol. 2000, 96: 224-228. 10.1016/S0029-7844(00)00864-4.

    Article  CAS  PubMed  Google Scholar 

  78. Li C, Gardy R, Seon BK, Duff SE, Abdalla S, Renehan A, O'Dwyer ST, Haboubi N, Kumar S: Both high intratumoral microvessel density determined using CD105 antibody and elevated plasma levels of CD105 in colorectal cancer patients correlate with poor prognosis. Br J Cancer. 2003, 88: 1424-1431. 10.1038/sj.bjc.6600874.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Saad RS, Liu YL, Nathan G, Celebrezze J, Medich D, Silverman JF: Endoglin [CD105] and vascular endothelial growth factor as prognostic markers in colorectal cancer. Mod Pathol. 2004, 17: 197-203. 10.1038/modpathol.3800034.

    Article  CAS  PubMed  Google Scholar 

  80. Salvesen HB, Gulluoglu MG, Stefansson I, Akslen LA: Significance of CD105 expression for tumour angiogenesis and prognosis in endometrial carcinomas. APMIS. 2003, 111: 1011-1018. 10.1111/j.1600-0463.2003.apm1111103.x.

    Article  PubMed  Google Scholar 

  81. Saad RS, Jasnosz KM, Tung MY, Silverman JF: Endoglin [CD105] expression in endometrial carcinoma. Int J Gynecol Pathol. 2003, 22: 248-253. 10.1097/01.PGP.0000070852.25718.37.

    Article  PubMed  Google Scholar 

  82. Straume O, Akslen LA: Expresson of vascular endothelial growth factor, its receptors [FLT-1, KDR] and TSP-1 related to microvessel density and patient outcome in vertical growth phase melanomas. Am J Pathol. 2001, 159: 223-235.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Adam M, Schmidt D, Wardelmann E, Wernert N, Albers P: Angiogenetic protooncogene ets-1 induced neovascularization is involved in the metastatic process of testicular germ cell tumors. Eur Urol. 2003, 44: 329-336. 10.1016/S0302-2838(03)00262-8.

    Article  CAS  PubMed  Google Scholar 

  84. Tanaka F, Otake Y, Yanagihara K, Kawano Y, Miyahara R, Li M, Yamada T, Hanaoka N, Inui K, Wada H: Evaluation of angiogenesis in non-small cell lung cancer: comparison between anti-CD34 antibody and anti-CD105 antibody. Clin Cancer Res. 2001, 7: 3410-3415.

    CAS  PubMed  Google Scholar 

  85. Yagasaki H, Kawata N, Takimoto Y, Nemoto N: Histopathological analysis of angiogenic factors in renal cell carcinoma. Int J Urol. 2003, 10: 220-227.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro and by the progetto Ricerca Finalizzata awarded by the Italian Ministry of Public Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michele Maio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fonsatti, E., Maio, M. Highlights on endoglin (CD105): from basic findings towards clinical applications in human cancer. J Transl Med 2, 18 (2004). https://doi.org/10.1186/1479-5876-2-18

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1479-5876-2-18

Keywords