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Cardiac myxoma and neural crests: a tense relationship
Journal Pre-proof Cardiac Myxoma and Neural Crests: a tense relationship Ivan Presta, Annalidia Donato, Domenico Chirchiglia, Natalia Malara, Giuseppe Donato PII:
S1054-8807(19)30328-X
DOI:
https://doi.org/10.1016/j.carpath.2019.107163
Reference:
CVP 107163
To appear in:
Cardiovascular Pathology
Received Date: 10 September 2019 Revised Date:
14 October 2019
Accepted Date: 15 October 2019
Please cite this article as: Presta I, Donato A, Chirchiglia D, Malara N, Donato G, Cardiac Myxoma and Neural Crests: a tense relationship, Cardiovascular Pathology, https://doi.org/10.1016/ j.carpath.2019.107163. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Abstract In cardiac myxomas the malignant transformation process, selecting incidental gene mutations and leading to loss of proliferation control, has not a so drastic effects being characterized by a slow growth of tumor mass, but frequently the particular location of lesion engrosses the high risk for health. For accurate cancer cell profiling it is important to establish the embryologic origin of malignant cells and their initial commitments, above all in the sight of therapeutic strategies and solutions. Here we advanced, for cardiac myxoma, the hypothesis of an origin from cardiac neural crests cells and we attempt to support it by an integrated discussion of current knowledge about embryological characteristics of neural crests cells and most recent studies focusing cardiac myxomas. We discuss the relationship between the basic plasticity of cardiac neural crests cells and some typical mutations arising in neoplastic lesions as well as the expression of typical cell markers of neural crests derivatives. Dysfunctions in proliferative and migratory programs, focused in other studies, are evaluated in the context of the topological and histopathological characteristics of cardiac myxomas.
REVIEW ARTICLE
Cardiac Myxoma and Neural Crests: a tense relationship Ivan Presta1, Annalidia Donato2, Domenico Chirchiglia2, Natalia Malara3, Giuseppe Donato1 1
Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy; Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy. 3 Department of Clinical and Experimental Medicine, University "Magna Graecia" of Catanzaro, Catanzaro, Italy. * Correspondence: [email protected]; Tel.: +39-0961-3694411 2
Abstract In cardiac myxomas the malignant transformation process, selecting incidental gene mutations and leading to loss of proliferation control, has not a so drastic effects being characterized by a slow growth of tumor mass, but frequently the particular location of lesion engrosses the high risk for health. For accurate cancer cell profiling it is important to establish the embryologic origin of malignant cells and their initial commitments, above all in the sight of therapeutic strategies and solutions. Here we advanced, for cardiac myxoma, the hypothesis of an origin from cardiac neural crests cells and we attempt to support it by an integrated discussion of current knowledge about embryological characteristics of neural crests cells and most recent studies focusing cardiac myxomas. We discuss the relationship between the basic plasticity of cardiac neural crests cells and some typical mutations arising in neoplastic lesions as well as the expression of typical cell markers of neural crests derivatives. Dysfunctions in proliferative and migratory programs, focused in other studies, are evaluated in the context of the topological and histopathological characteristics of cardiac myxomas.
Introduction Among the rare primary cardiac neoplasms, cardiac myxomas (CMs) are the most common. Usually sporadic and single, CMs arise from the foramen ovale zone, in the left atrium. Mainly detected in females, the mean age at the diagnosis is around 50 years. When are part of the Carney complex (CC), CMs can occur in younger patients, at multiple sites of the heart. Grossly, they may
present either as smooth, round and compact masses or as friable and villous vegetations. The location and general characteristics of CMs are important factors for clinical reports of the disease: in fact, such neoplasms may cause strokes, peripheral embolisms, syncope or sudden death. There is no explanation for constitutional symptoms like fever, high erythrocyte sedimentation rate and anemia when present. Notwithstanding the neoplastic nature is known from many years, there is uncertainty for histogenesis [1]. CMs derive from proliferating primitive cells that differentiate along endothelial/endocardial lines. For a long time, myxomas were thought to arise from microscopic endocardial/endothelial structures known as Prichard structures, little endocardial deformities with capillary spaces lined by plump endothelial cells, located into the fossa ovalis. Finally, this theory has been discredited by studies that showed no relationship between the seemingly age-related Prichard structures and myxomas. In turn, many data suggest that these formations might be the cardiac equivalent of cutaneous senile angioma. Subendothelial vasoformative reservoir cells or cardiomyocyte progenitors have been also suggested as possible precursors of CMs cells [2,3]. Formerly, a hypothetical origin of CMs from the Neural Crests (NCs) was suggested, based on the expression of calretinin in these tumors and was also considered specifically arising from the endocardial sensory nerve tissue [4]. Interestingly, a possible origin from NCs could be witnessed by the expression of other markers such as Ubiquitin carboxyl-terminal hydrolase isozyme L1 (PGP9.5), S100 proteins and neuron-specific enolase (NSE) [5]. Analyzing the most recent findings on cardiac neural crests and cardiac myxomas we are convinced that they corroborate the hypothesis of a pathogenetic link between these two entities. The NCs in humans arises during the third week of embryonal development between the neural plate and the adjacent non-neural ectoderm. Neural crest cells (NCCs) differentiated in this border region induced by various signals at the place where Bone Morphogenetic Protein (BMP) expression of neural plate is replaced by Wingless-Type MMTV Integration Site Family, Member 6 (Wnt6) expression of cutaneous ectoderm. After neural tube sealing, such cells come to reside in a
dorsal domain, along the neural tube, forming the NCs. The NCCs express a characteristic set of transcription factors, such as Snail2 (Slug), Sox9, Sox10, and FoxD3, all members of the so called “neural crest specifier genes” cluster [6]. NCCs are an embryonic-type cells, unique to vertebrates and forming numerous, different derivatives. NCs are designated as cranial, vagal, truncal and lumbosacral according the longitudinal position in the embryo. The cranial neural crests include prosencephalic, mesencephalic and anterior rhomboencephalic regions; posterior rhombencephalic region is incorporated into the vagal crests spanning somites 1–7; truncal crests include cervical and thoracic regions around the somites 8–28; lastly, lumbosacral crests correspond to the region located caudally beyond the 28th somite [7]. NCs can be considered as a fourth embryonic leaflet. The cells composing the four abovementioned subdivisions, can differentiate along an incredible number of lineages. NCCs native from different axial sections contribute to some distinct or overlapping differentiated cell types. Cranial NCCs contribute to connective tissue skeleton of the skull, Schwann cells, ciliary and cranial sensory ganglia. The enteric nervous system of the gut is generated by Vagal NCCs. Melanocytes arise from each of these subregions. In a chick study about parasympathetic innervation of the heart, Margaret Kirby and colleagues ablated cranial NCs region spanning occipital somites from 1 to 3, discovering that the embryos did not develop the aorticopulmonary septum [8]; this region has been later called “cardiac neural crests” (CNCs). NCCs from CNCs contribute to build the outflow tract and cardiac septum. Cephalic NCCs are the source of vascular smooth muscle cells and pericytes in an area of the circulatory system that extends distally from the cardiac outflow tract, along arteries and jugular veins to the distal capillary beds and choroid plexuses of the face and forebrain
[7]. NCCs from trunk region form adrenal medulla, Schwann cells, sensory and
sympathetic ganglia. Sacral NCCs, like their vagal counterpart, contribute to the enteric nervous system. Discussion
Published papers treating cardiac myxomas (CM) are generally rare and focusing on clinical observations, so the nature of such a lesion still remains not completely understood. CM is currently considered a neoplasm whose cells and stroma have common characteristics together with the endocardial
cushion
tissue.
This
tumor
generally
presents
a
myxoid
vascularized
mucopolysaccaridic stroma, containing stellate, fusiform or polygonal cells that can form pseudovascular structure with variable complexity [2,3,9,10]. It cannot be excluded a subsequent contribution to the tumor growth by mast cells, frequently populating this lesion and playing an active pro-angiogenic role, as it has been shown in other neoplasms [11–13]. There are some elements that make us consider a plausible origin of CMs from CNCs cells. CNC cells, arise from the postotic hindbrain and contribute to the formation of the tunica media of pharyngeal arch and artery-derived great vessels, the aorticopulmonary septum and the outflow tract of endocardial cushion [14,15]. In CMs is well known the occurrence of mutations inactivating the tumor suppressor gene PRKAR1A, both in sporadic and familiar forms. PRKAR1A encodes the regulatory subunit type 1α (R1α) of the protein kinase A (PKA) [16] and its inactivation could also support an abnormal activation of the PKA/mTOR axis which is of particular importance in neuro-regenerative and embryonic differentiation processes [17,18]. Interestingly, in a mice model with cardiacspecific PRKAR1A knock-out it has been shown the presence of myxomatous changes in the heart tissue despite the cardiac structures developed normally and mice die for cardiac failure during gestation [2]. The loss of PRKAR1A is known to trigger tumorigenesis or developmental troubles in NCs derivatives (Fig 1) [19]. Up to 10% of cardiac myxomas occur in the CC context, which is familial in 70% of cases with autosomal dominant inheritance. Germline inactivating mutations of PRKAR1A gene are found in 37% of patients with sporadic CC and in more than 70% of patients with familial CC. Clinically, CC is a multiple endocrine neoplasia and lentiginous syndrome, characterized by abnormal cutaneous and mucosal pigmentation and predominantly heart, skin and breast myxomas. Endocrine tumors can also be present such as pituitary adenomas, thyroid tumors, primary pigmented nodular
adrenocortical disease, testicular tumors and ovarian lesions, psammomatous melanotic schwannomas (PMSs), breast ductal adenomas, osteochondromyxomas, and other non-endocrine tumors [16]. Among the conditions listedabove , one can find many lesions with histogenesis linked to NCs like skin melanocytic pigmented lesions and PMSs. Patients with CC are also prone to develop multiple schwannomas though, more peculiarly, they develop PMS, an unusual schwannoma variant. Mice Prkar1a +/- develop nonpigmented schwannomas and fibroosseous bone lesions from six months of age; about a third of cells from these murine schwannomas is carrying a mutation in a PRKAR1A allele consistent with the postulated role of Prkar1a as a tumor suppressor. Moreover, mice with complete loss of Prkar1a in facial neural crest cells can develop schwannomas along the related region [20,21]. An evaluation of signaling molecules in such murine neoplasia showed that expression of neurofibromin was decreased, presumably via a post-translational mechanism [22]. Furthermore, a deregulation of protein kinase A (PKA) holoenzyme can alter cellular motility in various physiologic and pathologic processes [23–25]. Alterations of PRKAR1A gene could therefore result in both migration dysfunctions of cardiac NCCs and development of neoplasms. In this sense we can give an explanation regarding the development locations of cardiac CMs outside from the cardiac outflow tract and the rising of neoplasms with ectomesenchimal characteristics. In a recently published paper, Rudzinski and coworkers reported a case of a giant pericardial myxoma in proximity of the left main coronary, outside the cardiac cavities [26]. From a histologic point of view, differential diagnosis concerns were either the soft tissue myxoma or an ectopic cardiac myxoma. The authors favor this last interpretation, even if no immunohistochemical or genetic-molecular details are reported. It has recently confirmed that preotic NCs contribute to heart development [27]. Cellular elements originating from such a NCs compartment, are precursors of the smooth muscle cells of the coronary arteries, particularly in their proximal tract. These observations can support the particular location of the lesion described by Rudzinski et al., near to the left main coronary. CM cells also
express the MIA gene (melanoma inhibitory activity), a melanoma marker correlating with melanoma progression in vivo, although not expressed in melanocytes. The MIA protein interacts with cell adhesion receptors and extracellular matrix molecules promoting cell migration and invasion [5,28]. The ultimate migration of cardiac crest cells into the outflow tract is guided by semaphorin3C secretion and CNCs cells, in turn, express plexinA2 which heterodimerizes with neuropilins to create the receptor for semaphorine3C. It has previously been suggested that CMs cells can express both semaphorin3C and plexinA2 [29]. Notwithstanding such a datum need further confirmation and clarification: we have to keep in mind that semaphorin3C is thought to regulate migration but also proliferation of CNCs cells [30,31]. The semaphorin3C/PlexinA2 expressing neural crest cells could be attracted and in CM pushed to proliferate by an autocrine loop like it occurs in other types of tumors [32]. Regarding to the histopathologic characteristics of CMs a certain variability of the stroma composition is found, varying from lightly fibrous to metaplastic. The presence of glands in 2% of cardiac myxomas would indicate that they are not reactive lesions [2,9]. These findings might be both associated to the extraordinary versatility in the development of NC cells. Recently, Rogov and coworkers put forward the idea of considering CMs like hamartomas [33]. We partially agree with this view: we believe that this would be more properly defined choristoma and that probably the CNC cells in ectopic intracardiac location, give origin to such tumors. Finally, we can say that the aforementioned case report corroborates the hypothesis that looks at CMs as choristomas originated primarily by migration defects of CNCs cells and, on the other hand, no similar lesions can be find except for the cardiac region. Together with myocardiocytes, CMs express the heart and neural crest-derived transcript-1 (HAND1) gene [34], a member of the transcription factor subclass HAND, which encodes a basic helix-loop-helix transcription factor. Interestingly, it has been observed that mutations triggering HAND1 loss-of-function, enhance the susceptibility to tetralogy of Fallot, with a misplaced aorta as typical component [35]. Such a datum is not surprising since both Hand1 and Hand2 expression has been demonstrated in CNCs. The
expression of these genes is not detected until post-migration stage, suggesting a role in the patterning and differentiation of CNCs into OFT structures [36]. Conclusions The origin and histogenesis of cardiac myxoma is surely an intriguing enigma. Some data, which may have an elucidating potential, could be considered of complex interpretation or generating ambiguity and therefore need further investigation. Here we discussed some spread and incidental data, insinuating the idea that cells originating from neural crests, could be reasonable candidates to be the elements that give rise to this type of tumor. This is a theme that legitimize further studies exploiting specific molecular markers, aimed to confirm or exclude the relationship between CNCs and CMs. In conclusion, the relationship between NCs and CMs looks to be "tense" and difficult to be clarified. It must be finally proven, but several clues for its existence are evident. The main difficulties to prove it could derive from the enormous plasticity of NCCs and their ability to differentiate in neuronal, epithelial or mesenchymal phenotypes so that differentiation processes could mask the specific features of primitive cells. Finally, the study of the histogenesis of CMs could be beneficial for clarifying the role of still little-known signal pathways in the pathogenesis of cardiac or polysystemic diseases.
References
[1]
Basso C, Valente M, Thiene G. Cardiac Tumor Pathology. In: Cristina B, Gaetano T, Marialuisa V, editors. Card. Tumor Pathol., New York: Humana Press; 2013, p. 1–197. doi:10.1007/978-1-62703-143-1.
[2]
Di Vito A, Mignogna C, Donato G. The mysterious pathways of cardiac myxomas: A review of histogenesis, pathogenesis and pathology. Histopathology 2015;66:321–32. doi:10.1111/his.12531.
[3]
Donato G, Conforti F, Zuccalà V, Russo E, Maltese L, Perrotta I, et al. Expression of tenascin-c and CD44 receptors in cardiac myxomas. Cardiovasc Pathol 2009;18:173–7. doi:10.1016/j.carpath.2008.03.006.
[4]
Terracciano LM, Mhawech P, Suess K, D’Armiento M, Lehmann FS, Jundt G, et al. Calretinin as a marker for cardiac myxoma: Diagnostic and histogenetic considerations. Am J Clin Pathol 2000. doi:10.1309/NR6G-T872-F090-LBRW.
[5]
Singhal P, Luk A, Rao V, Butany J. Molecular basis of cardiac myxomas. Int J Mol Sci 2014;15:1315–37. doi:10.3390/ijms15011315.
[6]
Betancur P, Bronner-Fraser M, Sauka-Spengler T. Genomic code for Sox10 activation reveals a key regulatory enhancer for cranial neural crest . Proc Natl Acad Sci 2010;107:3570–5. doi:10.1073/pnas.0906596107.
[7]
Etchevers HC, Dupin E, Le Douarin NM. The diverse neural crest: From embryology to human pathology. Dev 2019;146:dev169821. doi:10.1242/dev.169821.
[8]
Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary septation. Science (80- ) 1983. doi:10.1126/science.6844926.
[9]
Burke A, Tavora F. The 2015 WHO Classification of tumors of the heart and pericardium. J Thorac Oncol 2016;11:441–52. doi:10.1016/j.jtho.2015.11.009.
[10] Donato G, Conforti F, Camastra C, Ammendola M, Donato A, Renzulli A. The role of mast cell tryptases in cardiac myxoma: Histogenesis and development of a challenging tumor. Oncol Lett 2014;8:379–83. doi:10.3892/ol.2014.2104. [11] Di Vito A, Santise G, Mignogna C, Chiefari E, Cardillo G, Presta I, et al. Innate immunity in cardiac myxomas and its pathological and clinical correlations. Innate Immun 2018. doi:10.1177/1753425917741678. [12] Di Vito A, Scali E, Ferraro G, Mignogna C, Presta I, Camastra C, et al. Elastofibroma dorsi: A histochemical and immunohistochemical study. Eur J Histochem 2015;59:7–16. doi:10.4081/ejh.2015.2459. [13] Ammendola M, Sacco R, Sammarco G, Donato G, Zuccalà V, Romano R, et al. Mast cells positive to tryptase and c-kit receptor expressing cells correlates with angiogenesis in gastric cancer patients surgically treated. Gastroenterol Res Pract 2013;2013. doi:10.1155/2013/703163. [14] Kirby ML, Hutson MR. Factors controlling cardiac neural crest cell migration. Cell Adhes Migr 2010. doi:10.4161/cam.4.4.13489. [15] Ma P, Gu S, Karunamuni GH, Jenkins MW, Watanabe M, Rollins AM. Cardiac neural crest ablation results in early endocardial cushion and hemodynamic flow abnormalities. Am J Physiol Circ Physiol 2016;311:H1150–9. doi:10.1152/ajpheart.00188.2016. [16] Kamilaris CDC, Faucz FR, Voutetakis A, Stratakis CA. Carney Complex. Exp Clin Endocrinol Diabetes 2019;127:156–64. doi:10.1055/a-0753-4943. [17] de Joussineau C, Sahut-Barnola I, Tissier F, Dumontet T, Drelon C, Batisse-Lignier M, et al. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD). Hum Mol Genet 2014;23:5418–28. doi:10.1093/hmg/ddu265. [18] Russo E, Follesa P, Citraro R, Camastra C, Donato A, Isola D, et al. The mTOR signaling pathway and neuronal stem/progenitor cell proliferation in the hippocampus are altered during the development of absence epilepsy in a genetic animal model. Neurol Sci 2014. doi:10.1007/s10072-014-1842-1. [19] Zhang M, Manchanda PK, Wu D, Wang Q, Kirschner LS. Knockdown of PRKAR1A , the
Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells. Mol Endocrinol 2014;28:295–307. doi:10.1210/me.2013-1152. [20] Kirschner LS, Kusewitt DF, Matyakhina L, Towns WH, Carney JA, Westphal H, et al. A mouse model for the carney complex tumor syndrome develops neoplasia in cyclic AMPresponsive tissues. Cancer Res 2005. doi:10.1158/0008-5472.CAN-05-0580. [21] Carroll SL. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms. Acta Neuropathol 2012;123:321–48. doi:10.1007/s00401-011-0928-6. [22] Jones GN, Towns II WH, Kirschner LS, Tep C, Sung OY, Mihai G, et al. Tissue-specific ablation of Prkar1a causes schwannomas by suppressing neurofibromatosis protein production. Neoplasia 2008. doi:10.1593/neo.08652. [23] Chávez-Vargas L, Adame-García SR, Cervantes-Villagrana RD, Castillo-Kauil A, Bruystens JGH, Fukuhara S, et al. Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor. J Biol Chem 2016;291:6182–99. doi:10.1074/jbc.m115.712216. [24] Sigloch FC, Burk UC, Biniossek ML, Brabletz T, Schilling O. miR-200c dampens cancer cell migration via regulation of protein kinase a subunits. Oncotarget 2015;6:23874–89. doi:10.18632/oncotarget.4381. [25] Gau D, Veon W, Shroff SG, Roy P, Fowler VM. The VASP-profilin1 (Pfn1) interaction is critical for efficient cell migration and is regulated by cell-substrate adhesion in a PKAdependent manner. J Biol Chem 2019;294:6972–85. doi:10.1074/jbc.RA118.005255. [26] Rudziński PN, Lubiszewska B, Różański J, Michałowska I, Kruk M, Kepka C, et al. Giant Intrapericardial Myxoma Adjacent to the Left Main Coronary Artery. Front Oncol 2018. doi:10.3389/fonc.2018.00540. [27] Arima Y, Miyagawa-Tomita S, Maeda K, Asai R, Seya D, Minoux M, et al. Preotic neural crest cells contribute to coronary artery smooth muscle involving endothelin signalling. Nat Commun 2012;3. doi:10.1038/ncomms2258. [28] Graf SA, Busch C, Bosserhoff AK, Besch R, Berking C. SOX10 promotes melanoma cell invasion by regulating melanoma inhibitory activity. J Invest Dermatol 2014;134:2212–20. doi:10.1038/jid.2014.128. [29] Di Vito A, Mignogna C, Malara N, Presta I, Cardillo G, Santise G, et al. Histogenesis of cardiac myxoma: the potential role of the cardiac neural crest. Ital J Anat Embryol 2017;122:176. doi:http://dx.doi.org/10.13128/IJAE-21473. [30] Scholl AM, Kirby ML. Signals controlling neural crest contributions to the heart. Wiley Interdiscip Rev Syst Biol Med 2009;1:220–7. doi:10.1002/wsbm.8. [31] Kodo K, Shibata S, Miyagawa-Tomita S, Ong SG, Takahashi H, Kume T, et al. Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development. Sci Rep 2017;7. doi:10.1038/s41598-017-06964-9. [32] Man J, Shoemake J, Zhou W, Fang X, Wu Q, Rizzo A, et al. Sema3C Promotes the Survival and Tumorigenicity of Glioma Stem Cells through Rac1 Activation. Cell Rep 2014;9:1812– 26. doi:10.1016/j.celrep.2014.10.055. [33] Rogov KA, Kaktursky LV ML. On the histogenesis of cardiac myxoma. Arkh Patol 2018;80:3–10. doi:doi: 10.17116/patol20188033-10. [34] Kodama H, Hirotani T, Suzuki Y, Ogawa S, Yamazaki K. Cardiomyogenic differentiation in
cardiac myxoma expressing lineage-specific transcription factors. Am J Pathol 2002;161:381–9. doi:10.1016/S0002-9440(10)64193-4. [35] Wang J, Hu XQ, Guo YH, Gu JY, Xu JH, Li YJ, et al. HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot. Pediatr Cardiol 2017;38:547–57. doi:10.1007/s00246-016-15478. [36] George RM, Firulli AB. Hand Factors in Cardiac Development. Anat Rec 2019;302:101–7. doi:10.1002/ar.23910.
Figure 1 A) A schematic draw of a human embryo around the sixth week of development. Here is shown the subdivision of the neural tube into different regions with evidence for cardiac neural crests (CNC). Cells migrate from CNC region which give rise to different components of the blood vessels and heart. A significant percentage of Carney Complex and cardiac myxomas both sporadic and familiar, is characterized by mutations in PRKAR1A gene. B) Mutations in the PRKAR1A gene, which encodes an isoform of regulatory subunits, lead to a persistent activation of PKA signaling, regardless to the stimuli convergent in cAMP generation. This would be the origin of dysfunctions in proliferation, migration and metabolism of CNC cells, leading to tipical tumorigenesis and ectopies.
S1054-8807(19)30328-X
DOI:
https://doi.org/10.1016/j.carpath.2019.107163
Reference:
CVP 107163
To appear in:
Cardiovascular Pathology
Received Date: 10 September 2019 Revised Date:
14 October 2019
Accepted Date: 15 October 2019
Please cite this article as: Presta I, Donato A, Chirchiglia D, Malara N, Donato G, Cardiac Myxoma and Neural Crests: a tense relationship, Cardiovascular Pathology, https://doi.org/10.1016/ j.carpath.2019.107163. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Abstract In cardiac myxomas the malignant transformation process, selecting incidental gene mutations and leading to loss of proliferation control, has not a so drastic effects being characterized by a slow growth of tumor mass, but frequently the particular location of lesion engrosses the high risk for health. For accurate cancer cell profiling it is important to establish the embryologic origin of malignant cells and their initial commitments, above all in the sight of therapeutic strategies and solutions. Here we advanced, for cardiac myxoma, the hypothesis of an origin from cardiac neural crests cells and we attempt to support it by an integrated discussion of current knowledge about embryological characteristics of neural crests cells and most recent studies focusing cardiac myxomas. We discuss the relationship between the basic plasticity of cardiac neural crests cells and some typical mutations arising in neoplastic lesions as well as the expression of typical cell markers of neural crests derivatives. Dysfunctions in proliferative and migratory programs, focused in other studies, are evaluated in the context of the topological and histopathological characteristics of cardiac myxomas.
REVIEW ARTICLE
Cardiac Myxoma and Neural Crests: a tense relationship Ivan Presta1, Annalidia Donato2, Domenico Chirchiglia2, Natalia Malara3, Giuseppe Donato1 1
Department of Health Sciences, University "Magna Græcia" of Catanzaro, Catanzaro, Italy; Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy. 3 Department of Clinical and Experimental Medicine, University "Magna Graecia" of Catanzaro, Catanzaro, Italy. * Correspondence: [email protected]; Tel.: +39-0961-3694411 2
Abstract In cardiac myxomas the malignant transformation process, selecting incidental gene mutations and leading to loss of proliferation control, has not a so drastic effects being characterized by a slow growth of tumor mass, but frequently the particular location of lesion engrosses the high risk for health. For accurate cancer cell profiling it is important to establish the embryologic origin of malignant cells and their initial commitments, above all in the sight of therapeutic strategies and solutions. Here we advanced, for cardiac myxoma, the hypothesis of an origin from cardiac neural crests cells and we attempt to support it by an integrated discussion of current knowledge about embryological characteristics of neural crests cells and most recent studies focusing cardiac myxomas. We discuss the relationship between the basic plasticity of cardiac neural crests cells and some typical mutations arising in neoplastic lesions as well as the expression of typical cell markers of neural crests derivatives. Dysfunctions in proliferative and migratory programs, focused in other studies, are evaluated in the context of the topological and histopathological characteristics of cardiac myxomas.
Introduction Among the rare primary cardiac neoplasms, cardiac myxomas (CMs) are the most common. Usually sporadic and single, CMs arise from the foramen ovale zone, in the left atrium. Mainly detected in females, the mean age at the diagnosis is around 50 years. When are part of the Carney complex (CC), CMs can occur in younger patients, at multiple sites of the heart. Grossly, they may
present either as smooth, round and compact masses or as friable and villous vegetations. The location and general characteristics of CMs are important factors for clinical reports of the disease: in fact, such neoplasms may cause strokes, peripheral embolisms, syncope or sudden death. There is no explanation for constitutional symptoms like fever, high erythrocyte sedimentation rate and anemia when present. Notwithstanding the neoplastic nature is known from many years, there is uncertainty for histogenesis [1]. CMs derive from proliferating primitive cells that differentiate along endothelial/endocardial lines. For a long time, myxomas were thought to arise from microscopic endocardial/endothelial structures known as Prichard structures, little endocardial deformities with capillary spaces lined by plump endothelial cells, located into the fossa ovalis. Finally, this theory has been discredited by studies that showed no relationship between the seemingly age-related Prichard structures and myxomas. In turn, many data suggest that these formations might be the cardiac equivalent of cutaneous senile angioma. Subendothelial vasoformative reservoir cells or cardiomyocyte progenitors have been also suggested as possible precursors of CMs cells [2,3]. Formerly, a hypothetical origin of CMs from the Neural Crests (NCs) was suggested, based on the expression of calretinin in these tumors and was also considered specifically arising from the endocardial sensory nerve tissue [4]. Interestingly, a possible origin from NCs could be witnessed by the expression of other markers such as Ubiquitin carboxyl-terminal hydrolase isozyme L1 (PGP9.5), S100 proteins and neuron-specific enolase (NSE) [5]. Analyzing the most recent findings on cardiac neural crests and cardiac myxomas we are convinced that they corroborate the hypothesis of a pathogenetic link between these two entities. The NCs in humans arises during the third week of embryonal development between the neural plate and the adjacent non-neural ectoderm. Neural crest cells (NCCs) differentiated in this border region induced by various signals at the place where Bone Morphogenetic Protein (BMP) expression of neural plate is replaced by Wingless-Type MMTV Integration Site Family, Member 6 (Wnt6) expression of cutaneous ectoderm. After neural tube sealing, such cells come to reside in a
dorsal domain, along the neural tube, forming the NCs. The NCCs express a characteristic set of transcription factors, such as Snail2 (Slug), Sox9, Sox10, and FoxD3, all members of the so called “neural crest specifier genes” cluster [6]. NCCs are an embryonic-type cells, unique to vertebrates and forming numerous, different derivatives. NCs are designated as cranial, vagal, truncal and lumbosacral according the longitudinal position in the embryo. The cranial neural crests include prosencephalic, mesencephalic and anterior rhomboencephalic regions; posterior rhombencephalic region is incorporated into the vagal crests spanning somites 1–7; truncal crests include cervical and thoracic regions around the somites 8–28; lastly, lumbosacral crests correspond to the region located caudally beyond the 28th somite [7]. NCs can be considered as a fourth embryonic leaflet. The cells composing the four abovementioned subdivisions, can differentiate along an incredible number of lineages. NCCs native from different axial sections contribute to some distinct or overlapping differentiated cell types. Cranial NCCs contribute to connective tissue skeleton of the skull, Schwann cells, ciliary and cranial sensory ganglia. The enteric nervous system of the gut is generated by Vagal NCCs. Melanocytes arise from each of these subregions. In a chick study about parasympathetic innervation of the heart, Margaret Kirby and colleagues ablated cranial NCs region spanning occipital somites from 1 to 3, discovering that the embryos did not develop the aorticopulmonary septum [8]; this region has been later called “cardiac neural crests” (CNCs). NCCs from CNCs contribute to build the outflow tract and cardiac septum. Cephalic NCCs are the source of vascular smooth muscle cells and pericytes in an area of the circulatory system that extends distally from the cardiac outflow tract, along arteries and jugular veins to the distal capillary beds and choroid plexuses of the face and forebrain
[7]. NCCs from trunk region form adrenal medulla, Schwann cells, sensory and
sympathetic ganglia. Sacral NCCs, like their vagal counterpart, contribute to the enteric nervous system. Discussion
Published papers treating cardiac myxomas (CM) are generally rare and focusing on clinical observations, so the nature of such a lesion still remains not completely understood. CM is currently considered a neoplasm whose cells and stroma have common characteristics together with the endocardial
cushion
tissue.
This
tumor
generally
presents
a
myxoid
vascularized
mucopolysaccaridic stroma, containing stellate, fusiform or polygonal cells that can form pseudovascular structure with variable complexity [2,3,9,10]. It cannot be excluded a subsequent contribution to the tumor growth by mast cells, frequently populating this lesion and playing an active pro-angiogenic role, as it has been shown in other neoplasms [11–13]. There are some elements that make us consider a plausible origin of CMs from CNCs cells. CNC cells, arise from the postotic hindbrain and contribute to the formation of the tunica media of pharyngeal arch and artery-derived great vessels, the aorticopulmonary septum and the outflow tract of endocardial cushion [14,15]. In CMs is well known the occurrence of mutations inactivating the tumor suppressor gene PRKAR1A, both in sporadic and familiar forms. PRKAR1A encodes the regulatory subunit type 1α (R1α) of the protein kinase A (PKA) [16] and its inactivation could also support an abnormal activation of the PKA/mTOR axis which is of particular importance in neuro-regenerative and embryonic differentiation processes [17,18]. Interestingly, in a mice model with cardiacspecific PRKAR1A knock-out it has been shown the presence of myxomatous changes in the heart tissue despite the cardiac structures developed normally and mice die for cardiac failure during gestation [2]. The loss of PRKAR1A is known to trigger tumorigenesis or developmental troubles in NCs derivatives (Fig 1) [19]. Up to 10% of cardiac myxomas occur in the CC context, which is familial in 70% of cases with autosomal dominant inheritance. Germline inactivating mutations of PRKAR1A gene are found in 37% of patients with sporadic CC and in more than 70% of patients with familial CC. Clinically, CC is a multiple endocrine neoplasia and lentiginous syndrome, characterized by abnormal cutaneous and mucosal pigmentation and predominantly heart, skin and breast myxomas. Endocrine tumors can also be present such as pituitary adenomas, thyroid tumors, primary pigmented nodular
adrenocortical disease, testicular tumors and ovarian lesions, psammomatous melanotic schwannomas (PMSs), breast ductal adenomas, osteochondromyxomas, and other non-endocrine tumors [16]. Among the conditions listedabove , one can find many lesions with histogenesis linked to NCs like skin melanocytic pigmented lesions and PMSs. Patients with CC are also prone to develop multiple schwannomas though, more peculiarly, they develop PMS, an unusual schwannoma variant. Mice Prkar1a +/- develop nonpigmented schwannomas and fibroosseous bone lesions from six months of age; about a third of cells from these murine schwannomas is carrying a mutation in a PRKAR1A allele consistent with the postulated role of Prkar1a as a tumor suppressor. Moreover, mice with complete loss of Prkar1a in facial neural crest cells can develop schwannomas along the related region [20,21]. An evaluation of signaling molecules in such murine neoplasia showed that expression of neurofibromin was decreased, presumably via a post-translational mechanism [22]. Furthermore, a deregulation of protein kinase A (PKA) holoenzyme can alter cellular motility in various physiologic and pathologic processes [23–25]. Alterations of PRKAR1A gene could therefore result in both migration dysfunctions of cardiac NCCs and development of neoplasms. In this sense we can give an explanation regarding the development locations of cardiac CMs outside from the cardiac outflow tract and the rising of neoplasms with ectomesenchimal characteristics. In a recently published paper, Rudzinski and coworkers reported a case of a giant pericardial myxoma in proximity of the left main coronary, outside the cardiac cavities [26]. From a histologic point of view, differential diagnosis concerns were either the soft tissue myxoma or an ectopic cardiac myxoma. The authors favor this last interpretation, even if no immunohistochemical or genetic-molecular details are reported. It has recently confirmed that preotic NCs contribute to heart development [27]. Cellular elements originating from such a NCs compartment, are precursors of the smooth muscle cells of the coronary arteries, particularly in their proximal tract. These observations can support the particular location of the lesion described by Rudzinski et al., near to the left main coronary. CM cells also
express the MIA gene (melanoma inhibitory activity), a melanoma marker correlating with melanoma progression in vivo, although not expressed in melanocytes. The MIA protein interacts with cell adhesion receptors and extracellular matrix molecules promoting cell migration and invasion [5,28]. The ultimate migration of cardiac crest cells into the outflow tract is guided by semaphorin3C secretion and CNCs cells, in turn, express plexinA2 which heterodimerizes with neuropilins to create the receptor for semaphorine3C. It has previously been suggested that CMs cells can express both semaphorin3C and plexinA2 [29]. Notwithstanding such a datum need further confirmation and clarification: we have to keep in mind that semaphorin3C is thought to regulate migration but also proliferation of CNCs cells [30,31]. The semaphorin3C/PlexinA2 expressing neural crest cells could be attracted and in CM pushed to proliferate by an autocrine loop like it occurs in other types of tumors [32]. Regarding to the histopathologic characteristics of CMs a certain variability of the stroma composition is found, varying from lightly fibrous to metaplastic. The presence of glands in 2% of cardiac myxomas would indicate that they are not reactive lesions [2,9]. These findings might be both associated to the extraordinary versatility in the development of NC cells. Recently, Rogov and coworkers put forward the idea of considering CMs like hamartomas [33]. We partially agree with this view: we believe that this would be more properly defined choristoma and that probably the CNC cells in ectopic intracardiac location, give origin to such tumors. Finally, we can say that the aforementioned case report corroborates the hypothesis that looks at CMs as choristomas originated primarily by migration defects of CNCs cells and, on the other hand, no similar lesions can be find except for the cardiac region. Together with myocardiocytes, CMs express the heart and neural crest-derived transcript-1 (HAND1) gene [34], a member of the transcription factor subclass HAND, which encodes a basic helix-loop-helix transcription factor. Interestingly, it has been observed that mutations triggering HAND1 loss-of-function, enhance the susceptibility to tetralogy of Fallot, with a misplaced aorta as typical component [35]. Such a datum is not surprising since both Hand1 and Hand2 expression has been demonstrated in CNCs. The
expression of these genes is not detected until post-migration stage, suggesting a role in the patterning and differentiation of CNCs into OFT structures [36]. Conclusions The origin and histogenesis of cardiac myxoma is surely an intriguing enigma. Some data, which may have an elucidating potential, could be considered of complex interpretation or generating ambiguity and therefore need further investigation. Here we discussed some spread and incidental data, insinuating the idea that cells originating from neural crests, could be reasonable candidates to be the elements that give rise to this type of tumor. This is a theme that legitimize further studies exploiting specific molecular markers, aimed to confirm or exclude the relationship between CNCs and CMs. In conclusion, the relationship between NCs and CMs looks to be "tense" and difficult to be clarified. It must be finally proven, but several clues for its existence are evident. The main difficulties to prove it could derive from the enormous plasticity of NCCs and their ability to differentiate in neuronal, epithelial or mesenchymal phenotypes so that differentiation processes could mask the specific features of primitive cells. Finally, the study of the histogenesis of CMs could be beneficial for clarifying the role of still little-known signal pathways in the pathogenesis of cardiac or polysystemic diseases.
References
[1]
Basso C, Valente M, Thiene G. Cardiac Tumor Pathology. In: Cristina B, Gaetano T, Marialuisa V, editors. Card. Tumor Pathol., New York: Humana Press; 2013, p. 1–197. doi:10.1007/978-1-62703-143-1.
[2]
Di Vito A, Mignogna C, Donato G. The mysterious pathways of cardiac myxomas: A review of histogenesis, pathogenesis and pathology. Histopathology 2015;66:321–32. doi:10.1111/his.12531.
[3]
Donato G, Conforti F, Zuccalà V, Russo E, Maltese L, Perrotta I, et al. Expression of tenascin-c and CD44 receptors in cardiac myxomas. Cardiovasc Pathol 2009;18:173–7. doi:10.1016/j.carpath.2008.03.006.
[4]
Terracciano LM, Mhawech P, Suess K, D’Armiento M, Lehmann FS, Jundt G, et al. Calretinin as a marker for cardiac myxoma: Diagnostic and histogenetic considerations. Am J Clin Pathol 2000. doi:10.1309/NR6G-T872-F090-LBRW.
[5]
Singhal P, Luk A, Rao V, Butany J. Molecular basis of cardiac myxomas. Int J Mol Sci 2014;15:1315–37. doi:10.3390/ijms15011315.
[6]
Betancur P, Bronner-Fraser M, Sauka-Spengler T. Genomic code for Sox10 activation reveals a key regulatory enhancer for cranial neural crest . Proc Natl Acad Sci 2010;107:3570–5. doi:10.1073/pnas.0906596107.
[7]
Etchevers HC, Dupin E, Le Douarin NM. The diverse neural crest: From embryology to human pathology. Dev 2019;146:dev169821. doi:10.1242/dev.169821.
[8]
Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary septation. Science (80- ) 1983. doi:10.1126/science.6844926.
[9]
Burke A, Tavora F. The 2015 WHO Classification of tumors of the heart and pericardium. J Thorac Oncol 2016;11:441–52. doi:10.1016/j.jtho.2015.11.009.
[10] Donato G, Conforti F, Camastra C, Ammendola M, Donato A, Renzulli A. The role of mast cell tryptases in cardiac myxoma: Histogenesis and development of a challenging tumor. Oncol Lett 2014;8:379–83. doi:10.3892/ol.2014.2104. [11] Di Vito A, Santise G, Mignogna C, Chiefari E, Cardillo G, Presta I, et al. Innate immunity in cardiac myxomas and its pathological and clinical correlations. Innate Immun 2018. doi:10.1177/1753425917741678. [12] Di Vito A, Scali E, Ferraro G, Mignogna C, Presta I, Camastra C, et al. Elastofibroma dorsi: A histochemical and immunohistochemical study. Eur J Histochem 2015;59:7–16. doi:10.4081/ejh.2015.2459. [13] Ammendola M, Sacco R, Sammarco G, Donato G, Zuccalà V, Romano R, et al. Mast cells positive to tryptase and c-kit receptor expressing cells correlates with angiogenesis in gastric cancer patients surgically treated. Gastroenterol Res Pract 2013;2013. doi:10.1155/2013/703163. [14] Kirby ML, Hutson MR. Factors controlling cardiac neural crest cell migration. Cell Adhes Migr 2010. doi:10.4161/cam.4.4.13489. [15] Ma P, Gu S, Karunamuni GH, Jenkins MW, Watanabe M, Rollins AM. Cardiac neural crest ablation results in early endocardial cushion and hemodynamic flow abnormalities. Am J Physiol Circ Physiol 2016;311:H1150–9. doi:10.1152/ajpheart.00188.2016. [16] Kamilaris CDC, Faucz FR, Voutetakis A, Stratakis CA. Carney Complex. Exp Clin Endocrinol Diabetes 2019;127:156–64. doi:10.1055/a-0753-4943. [17] de Joussineau C, Sahut-Barnola I, Tissier F, Dumontet T, Drelon C, Batisse-Lignier M, et al. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD). Hum Mol Genet 2014;23:5418–28. doi:10.1093/hmg/ddu265. [18] Russo E, Follesa P, Citraro R, Camastra C, Donato A, Isola D, et al. The mTOR signaling pathway and neuronal stem/progenitor cell proliferation in the hippocampus are altered during the development of absence epilepsy in a genetic animal model. Neurol Sci 2014. doi:10.1007/s10072-014-1842-1. [19] Zhang M, Manchanda PK, Wu D, Wang Q, Kirschner LS. Knockdown of PRKAR1A , the
Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells. Mol Endocrinol 2014;28:295–307. doi:10.1210/me.2013-1152. [20] Kirschner LS, Kusewitt DF, Matyakhina L, Towns WH, Carney JA, Westphal H, et al. A mouse model for the carney complex tumor syndrome develops neoplasia in cyclic AMPresponsive tissues. Cancer Res 2005. doi:10.1158/0008-5472.CAN-05-0580. [21] Carroll SL. Molecular mechanisms promoting the pathogenesis of Schwann cell neoplasms. Acta Neuropathol 2012;123:321–48. doi:10.1007/s00401-011-0928-6. [22] Jones GN, Towns II WH, Kirschner LS, Tep C, Sung OY, Mihai G, et al. Tissue-specific ablation of Prkar1a causes schwannomas by suppressing neurofibromatosis protein production. Neoplasia 2008. doi:10.1593/neo.08652. [23] Chávez-Vargas L, Adame-García SR, Cervantes-Villagrana RD, Castillo-Kauil A, Bruystens JGH, Fukuhara S, et al. Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor. J Biol Chem 2016;291:6182–99. doi:10.1074/jbc.m115.712216. [24] Sigloch FC, Burk UC, Biniossek ML, Brabletz T, Schilling O. miR-200c dampens cancer cell migration via regulation of protein kinase a subunits. Oncotarget 2015;6:23874–89. doi:10.18632/oncotarget.4381. [25] Gau D, Veon W, Shroff SG, Roy P, Fowler VM. The VASP-profilin1 (Pfn1) interaction is critical for efficient cell migration and is regulated by cell-substrate adhesion in a PKAdependent manner. J Biol Chem 2019;294:6972–85. doi:10.1074/jbc.RA118.005255. [26] Rudziński PN, Lubiszewska B, Różański J, Michałowska I, Kruk M, Kepka C, et al. Giant Intrapericardial Myxoma Adjacent to the Left Main Coronary Artery. Front Oncol 2018. doi:10.3389/fonc.2018.00540. [27] Arima Y, Miyagawa-Tomita S, Maeda K, Asai R, Seya D, Minoux M, et al. Preotic neural crest cells contribute to coronary artery smooth muscle involving endothelin signalling. Nat Commun 2012;3. doi:10.1038/ncomms2258. [28] Graf SA, Busch C, Bosserhoff AK, Besch R, Berking C. SOX10 promotes melanoma cell invasion by regulating melanoma inhibitory activity. J Invest Dermatol 2014;134:2212–20. doi:10.1038/jid.2014.128. [29] Di Vito A, Mignogna C, Malara N, Presta I, Cardillo G, Santise G, et al. Histogenesis of cardiac myxoma: the potential role of the cardiac neural crest. Ital J Anat Embryol 2017;122:176. doi:http://dx.doi.org/10.13128/IJAE-21473. [30] Scholl AM, Kirby ML. Signals controlling neural crest contributions to the heart. Wiley Interdiscip Rev Syst Biol Med 2009;1:220–7. doi:10.1002/wsbm.8. [31] Kodo K, Shibata S, Miyagawa-Tomita S, Ong SG, Takahashi H, Kume T, et al. Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development. Sci Rep 2017;7. doi:10.1038/s41598-017-06964-9. [32] Man J, Shoemake J, Zhou W, Fang X, Wu Q, Rizzo A, et al. Sema3C Promotes the Survival and Tumorigenicity of Glioma Stem Cells through Rac1 Activation. Cell Rep 2014;9:1812– 26. doi:10.1016/j.celrep.2014.10.055. [33] Rogov KA, Kaktursky LV ML. On the histogenesis of cardiac myxoma. Arkh Patol 2018;80:3–10. doi:doi: 10.17116/patol20188033-10. [34] Kodama H, Hirotani T, Suzuki Y, Ogawa S, Yamazaki K. Cardiomyogenic differentiation in
cardiac myxoma expressing lineage-specific transcription factors. Am J Pathol 2002;161:381–9. doi:10.1016/S0002-9440(10)64193-4. [35] Wang J, Hu XQ, Guo YH, Gu JY, Xu JH, Li YJ, et al. HAND1 Loss-of-Function Mutation Causes Tetralogy of Fallot. Pediatr Cardiol 2017;38:547–57. doi:10.1007/s00246-016-15478. [36] George RM, Firulli AB. Hand Factors in Cardiac Development. Anat Rec 2019;302:101–7. doi:10.1002/ar.23910.
Figure 1 A) A schematic draw of a human embryo around the sixth week of development. Here is shown the subdivision of the neural tube into different regions with evidence for cardiac neural crests (CNC). Cells migrate from CNC region which give rise to different components of the blood vessels and heart. A significant percentage of Carney Complex and cardiac myxomas both sporadic and familiar, is characterized by mutations in PRKAR1A gene. B) Mutations in the PRKAR1A gene, which encodes an isoform of regulatory subunits, lead to a persistent activation of PKA signaling, regardless to the stimuli convergent in cAMP generation. This would be the origin of dysfunctions in proliferation, migration and metabolism of CNC cells, leading to tipical tumorigenesis and ectopies.