Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: Implications for biologic behavior and response to therapy

doi:10.1067/mjd.2000.111632

Journal of the American Academy of Dermatology

Volume 44, Issue 2, Part 1, February 2001, Pages 193-197

https://doi.org/10.1067/mjd.2000.111632 Get rights and content

Abstract

Background: Tumors of endothelium range from benign hemangiomas of infancy to highly malignant angiosarcomas of the elderly. Hemangiomas are the most common tumors in infants and may affect up to 10% of all children. The biologic behavior of these lesions ranges from self-resolving, in the case of hemangiomas and pyogenic granulomas, to lethal metastatic neoplasms in the case of angiosarcoma. Although the clinical outcomes of these diseases are easily distinguished, the biologic basis for these differences is not well understood. Activation of mitogen-activated protein kinase (MAPK) is an important signal transduction mechanism that may predict response of a tumor to chemotherapy. Objective: Our purpose was to examine expression of phosphorylated (activated) MAPK in hemangiomas of infancy, pyogenic granulomas, hemangioendotheliomas, and angiosarcomas to determine whether phosphorylated MAPK was expressed in endothelial tumors. In addition, we examined endothelial tumors of infectious origin, Kaposi’s sarcoma, and verruga peruana. Methods: Skin sections from benign and malignant endothelial tumors, including hemangioma of infancy, angiosarcoma, and infectious endothelial lesions (Kaposi’s sarcoma, verruga peruana) were stained with an antibody specific for phosphorylated MAPK. Results: We demonstrated strong expression of phosphorylated MAPK in benign endothelial tumors, including capillary hemangioma of infancy and pyogenic granuloma, and greatly decreased expression in angiosarcoma. In addition, infectious endothelial tumors stained strongly with this antibody, similar to benign tumors. The presence of immunoreactive phosphorylated MAPK appears to be inversely correlated with degree of malignancy. Conclusion: We demonstrate that the use of antibodies specific for signal transduction pathways is feasible in paraffin-fixed tissue. Thus the activity of a given signal transduction pathway can be ascertained in a biopsy specimen. Immunohistochemistry for phosphorylated MAPK may help the pathologist distinguish benign from malignant endothelial processes and thus guide therapy. (J Am Acad Dermatol 10.1067/mjd.2000.111632.)

Section snippets

Material and methods

We studied 49 vascular lesions including juvenile capillary hemangioma (n = 7), pyogenic granuloma (n = 7), hemangioendothelioma (n = 14), Kaposi’s sarcoma (n = 9), cutaneous angiosarcoma (n = 7), and verruga peruana (n = 4) from the surgical pathology archival files in the Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, the Department of Pathology Universidad Nacionale Cayetano Heredia, Lima, Peru, and from the consultation cases of one of the authors (S. W. W.)

Results

Table I indicates the expression of phosphorylated MAPK as percentage of total endothelial cells in benign, infectious, and malignant endothelial proliferations, respectively. Juvenile capillary hemangiomas, pyogenic granulomas, and verruga peruana demonstrated a high percentage of positivity (>25%) of phosphorylated MAPK-positive endothelial cells. This was also the case in Kaposi’s sarcoma (Fig 1, Table I).

. Immunohistochemistry of representative endothelial tumors with an antibody specific

Discussion

Endothelial tumors are a common but clinically diverse group of tumors, which affect patients of all ages. Children are most commonly affected with benign hemangiomas of infancy, but tumors of intermediate- and high-grade malignancy can masquerade as hemangiomas. Clinically, hemangioendothelioma and angiosarcoma may appear similar, but do not spontaneously regress or regress in response to mild antiangiogenic agents, such as glucocorticoids or interferon alfa.15, 17 The tumors that fail to

References (30)

L Requena et al.
Cutaneous vascular proliferations. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms
J Am Acad Dermatol
(1998)
S Gonzalez et al.
Treatment of pyogenic granulomas with the 585 nm pulsed dye laser
J Am Acad Dermatol
(1996)
CJ Cockerell et al.
Clinical, histologic, microbiologic, and biochemical characterization of the causative agent of bacillary (epithelioid) angiomatosis: a rickettsial illness with features of bartonellosis
J Invest Dermatol
(1991)
DH Spach et al.
Bartonella-associated infections
Infect Dis Clin North Am
(1998)
J Kroll et al.
The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells
J Biol Chem
(1997)
AV Khokhlatchev et al.
Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation
Cell
(1998)
PE North et al.
GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas
Hum Pathol
(2000)
JW Mandell et al.
In situ visualization of intratumor growth factor signaling: immunohistochemical localization of activated ERK/MAP kinase in glial neoplasms
Am J Pathol
(1998)
JL Arbiser et al.
The antiangiogenic agents TNP-470 and 2-methoxyestradiol inhibit the growth of angiosarcoma in mice
J Am Acad Dermatol
(1999)
WH Morrison et al.
Cutaneous angiosarcoma of the head and neck: a therapeutic dilemma
Cancer
(1995)

BA Drolet et al.

Hemangiomas in children

N Engl J Med

(1999)

K Takahashi et al.

Cellular markers that distinguish the phases of hemangioma during infancy and childhood

J Clin Invest

(1994)

RA Ezekowitz et al.

Interferon alfa-2a therapy for life-threatening hemangiomas of infancy

N Engl J Med

(1992)

O Enjolras et al.

The current management of vascular birthmarks

Pediatr Dermatol

(1993)

K Shimizu et al.

Inducible nitric oxide synthase is expressed in granuloma pyogenicum

Br J Dermatol

(1998)

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This observation implies that the Erk1/2 signaling pathway has a crucial role in the differentiation of HemSCs, including their vasculogenesis and adipogenesis. The activation of Erk1/2 in proliferating hemangioma tissues was reported in several previous studies (Arbiser et al., 2001; Boscolo et al., 2011). Moreover, the activation of Erk1/2 in HemSCs facilitates their endothelial differentiation (Greenberger et al., 2011).
Macrophage infiltration has been implicated in infantile hemangioma (IH), the most common tumor of infancy. However, the exact role of macrophages in IH remains unknown. This study aims to clarify the functional significance of macrophages in the progression of IH. The distribution of macrophages in human IH was analyzed, and our results revealed that polarized macrophages were more prevalent in proliferating IHs than in involuting IHs, which was consistent with the increased macrophage-related cytokines in proliferating IHs. In vitro results further demonstrated that polarized macrophages effectively promoted the proliferation of hemangioma stem cells (HemSCs) and suppressed their adipogenesis in an Akt- and extracellular signal-regulated kinase 1/2 (Erk1/2)-dependent manner. Moreover, M2- but not M1-polarized macrophages promoted the endothelial differentiation of HemSCs. Furthermore, mixing macrophages in a murine hemangioma model elevated microvessel density and postponed fat tissue formation, which was concomitant with the activation of Akt and Erk1/2 signals. Cluster analysis revealed a close correlation among the macrophage markers, Ki67, vascular endothelial growth factor (VEGF), p-Akt, and p-Erk1/2 in human IH tissues. Collectively, our results suggest that macrophages in IH contribute to tumor progression by promoting the proliferation and endothelial differentiation while suppressing the adipogenesis of HemSCs. These findings indicate that targeting the infiltrating macrophages in IH is a promising therapeutic approach to accelerate IH regression.
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Immunohistochemistry was performed on 19 skin biopsy samples from 11 patients with PWS.
c-Jun N-terminal kinase, extracellular signal-regulated kinase, and P70 ribosomal S6 kinase in pediatric and adult PWS blood vessels were consecutively activated. Activation of AKT and phosphatidylinositol 3-kinase was found in many adult hypertrophic PWS blood vessels but not in infants. Phosphoinositide phospholipase C γ subunit showed strong activation in nodular PWS blood vessels.
Infantile PWS sample size was small.
Our data suggest a subsequent activation profile of various kinases during different stages of PWS: (1) c-Jun N-terminal and extracellular signal-regulated kinases are firstly and consecutively activated in all PWS tissues, which may contribute to both the pathogenesis and progressive development of PWS; (2) AKT and phosphatidylinositol 3-kinase are subsequently activated, and are involved in the hypertrophic development of PWS blood vessels; and (3) phosphoinositide phospholipase C γ subunit is activated in the most advanced stage of PWS and may participate in nodular formation.
Immunohistochemical Analysis of the Akt/mTOR/4E-BP1 Signalling Pathway in Canine Haemangiomas and Haemangiosarcomas
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The activation of eIF4E is regulated not only by the Akt/mTOR/4E-BP1 pathway but also by Mnk1, a MAPK-dependent kinase (Waskiewicz et al., 1999). The MAPK pathway is reported to be highly activated in human HAs, but not in human angiosarcomas (Arbiser et al., 2001). Therefore, eIF4E-positive cases without 4E-BP1 activation may reflect the activation of the MAPK pathway, especially in cases of canine HA.
The specific signalling pathways that are deregulated in canine endothelial tumours have not yet fully elucidated. Therefore, the aim of the present study was to examine activation of the Akt/mammalian target of rapamycin (mTOR)/eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) signalling pathway in spontaneously arising canine haemangiomas (HAs) and haemangiosarcomas (HSAs) in order to identify novel molecular targets for treatment. Surgically-resected samples of HA (n = 27), HSA (n = 37), granulation tissue (n = 4) and normal skin (n = 4) were investigated by immunohistochemistry. Approximately 80% of the HSA samples had moderate to intense expression of phosphorylated Akt at Ser473 (p-Akt Ser473), p-Akt Thr308, p-4E-BP1 Thr37/46 and eukaryotic initiation factor 4E, which was significantly higher than in the HAs and was similar to the expression in activated endothelial cells (ECs). Although p-mTOR complex1 (p-mTORC1) Ser2448 was expressed by most of the activated ECs, only 35% of the HSA samples had weak to moderate expression. Because mTORC2 and phosphorylates Akt Ser473 was activated in HSA samples, the present findings suggest that the mTORC2/Akt/4E-BP1 pathway, regulated independently of mTORC1, may be important for targeting therapy in canine HSAs.
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Furthermore, MAPKs are often associated with pathologic responses, such as stress, apoptosis, inflammation, and cell proliferation.5,6 In terms of vascular conditions, differential expression of active MAPKs was noticed in several types of hemangiomas,7 the most common vascular tumor of infancy and childhood,8 and the presence of immunoreactive phosphorylated MAPK inversely correlate with degree of malignancy.7 Therefore, from a drug discovery standpoint, vascular specific components of MAPKs cascade are promising drug targets.6
Mitogen-activated protein kinases play an integral role in several cellular processes. To regulate mitogen-activated protein kinases, cells express members of a counteracting group of proteins called phosphatases. In this study, we have identified a specific role that one member of this family of phosphatases, dual-specific phosphatase-5 (Dusp-5) plays in vascular development in vivo. We have determined that dusp-5 is expressed in angioblasts and in established vasculature and that it counteracts the function of a serine threonine kinase, Snrk-1, which also plays a functional role in angioblast development. Together, Dusp-5 and Snrk-1 control angioblast populations in the lateral plate mesoderm with Dusp-5 functioning downstream of Snrk-1. Importantly, mutations in dusp-5 and snrk-1 have been identified in affected tissues of patients with vascular anomalies, implicating the Snrk-1–Dusp-5 signaling pathway in human disease.

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^☆: Supported by the Society for Pediatric Dermatology, the Dermatology Foundation, and the Thomas B. Fitzpatrick KAO Award (to J. L. A.), American Skin Association and National Institute of Arthritis, Musculoskeletal and Skin Diseases grants R03AR44947 (to J. L. A.), Emory Skin Disease Research Core Center grants P30 AR 42687 and KO8 AR02030 (to J. L. A.).

^☆☆: Reprint requests: Jack L. Arbiser, MD, PhD, Department of Dermatology, Emory University School of Medicine, WMB 5309, Atlanta, GA 30322. E-mail: [email protected]

^★: Published November 17, 2000.

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ReportDifferential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: Implications for biologic behavior and response to therapy☆,☆☆,★

Abstract

Section snippets

Material and methods

Results

Discussion

J Am Acad Dermatol

J Am Acad Dermatol

J Invest Dermatol

Infect Dis Clin North Am

J Biol Chem

Cell

Hum Pathol

Am J Pathol

J Am Acad Dermatol

Cutaneous angiosarcoma of the head and neck: a therapeutic dilemma

Cancer

Hemangiomas in children

N Engl J Med

Cellular markers that distinguish the phases of hemangioma during infancy and childhood

J Clin Invest

Interferon alfa-2a therapy for life-threatening hemangiomas of infancy

N Engl J Med

The current management of vascular birthmarks

Pediatr Dermatol

Inducible nitric oxide synthase is expressed in granuloma pyogenicum

Br J Dermatol

Report
Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: Implications for biologic behavior and response to therapy☆,☆☆,★