Novel animal model of soft tissue tumor due to aberrant hedgehog signaling activation in pericyte lineage.
Bone resorption
Genetic lineage tracing
Hedgehog signal
Pericyte
Soft tissue tumor
Journal
Cell and tissue research
ISSN: 1432-0878
Titre abrégé: Cell Tissue Res
Pays: Germany
ID NLM: 0417625
Informations de publication
Date de publication:
Apr 2022
Apr 2022
Historique:
received:
02
08
2021
accepted:
10
01
2022
pubmed:
25
1
2022
medline:
6
4
2022
entrez:
24
1
2022
Statut:
ppublish
Résumé
Pericytes are pluripotent cells that enclose the endothelium of small blood vessels in the whole body. These cells are thought to play a limited role in vascular development and blood pressure regulation; however, current evidence from numerous studies suggests several significant biologic aspects of pericytes in animals. One viewpoint is that pericytes are also known as potential cellular origin of multiple soft tissue tumors. Experimental evidence of the cellular origin of pericytic tumors is still insufficient, however, and their molecular pathogenesis is poorly understood. Here, we used a conditional constitutively active Smoothened allele (Rosa-SmoM2) and Cre recombinase mice to activate hedgehog (Hh) signaling, exclusively in the monocyte/macrophage and osteoclast lineage (LysMcre) or in RANK expressing cells (RANKcre) that are recognized as osteoclast precursor cells. Mice conditionally expressing SmoM2 with LysMcre displayed no significant skeletal phenotype; surprisingly, however, RANKcre; Rosa-SmoM2 mice frequently developed progressive soft tissue tumors in regions of the leg. Genetic lineage tracing analysis uncovered a new domain of RANKcre-expressing cells in the skeletal muscle interstitial cells that display markers consistent with vascular pericytes. Neoplasms arising from these cells showed increased expression of Matrix metalloproteinases (MMPs) that are molecular indicators of malignancy. Moreover, the tumors displayed strong bone invasive potency associated with osteoclastic bone resorption. Thus, these findings provide a novel insight into tumor pathology: Hh signal activated-pericytes can be a potential cellular origin of multiple soft tissue tumors.
Identifiants
pubmed: 35072792
doi: 10.1007/s00441-022-03578-0
pii: 10.1007/s00441-022-03578-0
doi:
Substances chimiques
Hedgehog Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
63-73Subventions
Organisme : kakenhi
ID : 18K06832
Organisme : kakenhi
ID : 20H03458
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Antonescu CR, Agaram NP, Sung YS, Zhang L, Swanson D, Dickson BC (2018) A distinct malignant epithelioid neoplasm with GLI1 gene rearrangements, frequent S100 protein expression, and metastatic potential: expanding the spectrum of pathologic entities with ACTB/MALAT1/PTCH1-GLI1 fusions. Am J Surg Pathol 42:553–560
pubmed: 29309307
pmcid: 5844813
Armah HB, Parwani AV (2009) Perivascular epithelioid cell tumor. Arch Pathol Lab Med 133:648–654
pubmed: 19391667
Armulik A, Genove G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21:193–215
pubmed: 21839917
Cannonier SA, Gonzales CB, Ely K, Guelcher SA, Sterling JA (2016) Hedgehog and TGFbeta signaling converge on Gli2 to control bony invasion and bone destruction in oral squamous cell carcinoma. Oncotarget 7:76062–76075
pubmed: 27738315
pmcid: 5340177
Cannonier SA, Sterling JA (2015) The role of hedgehog signaling in tumor induced bone disease. Cancers (basel) 7:1658–1683
Caplan AI (2008) All MSCs are pericytes? Cell Stem Cell 3:229–230
pubmed: 18786406
Chang L, Zhao D, Liu HB, Wang QS, Zhang P, Li CL, Du WZ, Wang HJ, Liu X, Zhang ZR, Jiang CL (2015) Activation of sonic hedgehog signaling enhances cell migration and invasion by induction of matrix metalloproteinase-2 and -9 via the phosphoinositide-3 kinase/AKT signaling pathway in glioblastoma. Mol Med Rep 12:6702–6710
pubmed: 26299938
pmcid: 4626128
Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I (1999) Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res 8:265–277
pubmed: 10621974
Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Peault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313
pubmed: 18786417
Dahlen A, Fletcher CD, Mertens F, Fletcher JA, Perez-Atayde AR, Hicks MJ, Debiec-Rychter M, Sciot R, Wejde J, Wedin R, Mandahl N, Panagopoulos I (2004) activation of the GLI oncogene through fusion with the beta-actin gene (ACTB) in a group of distinctive pericytic neoplasms: pericytoma with t(7;12). Am J Pathol 164:1645–1653
pubmed: 15111311
pmcid: 1615655
Das S, Samant RS, Shevde LA (2011) Hedgehog signaling induced by breast cancer cells promotes osteoclastogenesis and osteolysis. J Biol Chem 286:9612–9622
pubmed: 21169638
Das S, Samant RS, Shevde LA (2012) The hedgehog pathway conditions the bone microenvironment for osteolytic metastasis of breast cancer. Int J Breast Cancer 2012:298623
Dellavalle A, Sampaolesi M, Tonlorenzi R, Tagliafico E, Sacchetti B, Perani L, Innocenzi A, Galvez BG, Messina G, Morosetti R, Li S, Belicchi M, Peretti G, Chamberlain JS, Wright WE, Torrente Y, Ferrari S, Bianco P, Cossu G (2007) Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nat Cell Biol 9:255–267
pubmed: 17293855
Drummond CJ, Hanna JA, Garcia MR, Devine DJ, Heyrana AJ, Finkelstein D, Rehg JE, Hatley ME (2018) Hedgehog pathway drives fusion-negative rhabdomyosarcoma initiated from non-myogenic endothelial progenitors. Cancer Cell 33:108–124 e105
Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Griffin-Jones C, Canfield AE (2004) Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110:2226–2232
pubmed: 15466630
Feng X, Teitelbaum SL (2013) Osteoclasts: new insights. Bone Res 1:11–26
pubmed: 26273491
Folpe AL, Fanburg-Smith JC, Miettinen M, Weiss SW (2001) Atypical and malignant glomus tumors: analysis of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol 25:1–12
pubmed: 11145243
Gailani MR, Stahle-Backdahl M, Leffell DJ, Glynn M, Zaphiropoulos PG, Pressman C, Unden AB, Dean M, Brash DE, Bale AE, Toftgard R (1996) The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 14:78–81
pubmed: 8782823
Hahn H, Wojnowski L, Specht K, Kappler R, Calzada-Wack J, Potter D, Zimmer A, Muller U, Samson E, Quintanilla-Martinez L, Zimmer A (2000) Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J Biol Chem 275:28341–28344
pubmed: 10884376
Haraguchi R, Kitazawa R, Mori K, Tachibana R, Kiyonari H, Imai Y, Abe T, Kitazawa S (2016) sFRP4-dependent Wnt signal modulation is critical for bone remodeling during postnatal development and age-related bone loss. Sci Rep 6:25198
pubmed: 27117872
pmcid: 4846872
Haraguchi R, Kitazawa R, Murashima A, Yamada G, Kitazawa S (2017) Developmental contribution of Wnt-signal-responsive cells to mouse reproductive tract formation. Acta Histochem Cytochem 50:127–133
pubmed: 28928542
pmcid: 5593815
Haraguchi R, Kohara Y, Matsubayashi K, Kitazawa R, Kitazawa S (2020) New insights into the pathogenesis of diabetic nephropathy: proximal renal tubules are primary target of oxidative stress in diabetic kidney. Acta Histochem Cytochem 53:21–31
pubmed: 32410750
pmcid: 7212204
Hatley ME, Tang W, Garcia MR, Finkelstein D, Millay DP, Liu N, Graff J, Galindo RL, Olson EN (2012) A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell 22:536–546
pubmed: 23079662
pmcid: 3479681
Honami T, Shimo T, Okui T, Kurio N, Hassan NM, Iwamoto M, Sasaki A (2012) Sonic hedgehog signaling promotes growth of oral squamous cell carcinoma cells associated with bone destruction. Oral Oncol 48:49–55
pubmed: 21945071
Jeng KS, Chang CF, Lin SS (2020) Sonic hedgehog signaling in organogenesis, tumors, and tumor microenvironments. Int J Mol Sci 21:758
pmcid: 7037908
Jeong J, Mao J, Tenzen T, Kottmann AH, McMahon AP (2004) Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev 18:937–951
pubmed: 15107405
pmcid: 395852
Kawakami R, Nakagami H, Noma T, Ohmori K, Kohno M, Morishita R (2016) RANKL system in vascular and valve calcification with aging. Inflamm Regen 36:10
pubmed: 29259683
pmcid: 5725909
Kobayashi N, Takahashi D, Takano S, Kimura S, Hase K (2019) The roles of Peyer’s patches and microfold cells in the gut immune system: relevance to autoimmune diseases. Front Immunol 10:2345
pubmed: 31649668
pmcid: 6794464
Kong JH, Siebold C, Rohatgi R (2019) Biochemical mechanisms of vertebrate hedgehog signaling. Development 146:dev166892
Kuo FY, Lin HC, Eng HL, Huang CC (2005) Sinonasal hemangiopericytoma-like tumor with true pericytic myoid differentiation: a clinicopathologic and immunohistochemical study of five cases. Head Neck 27:124–129
pubmed: 15529319
Lam CW, Xie J, To KF, Ng HK, Lee KC, Yuen NW, Lim PL, Chan LY, Tong SF, McCormick F (1999) A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 18:833–836
pubmed: 9989836
Latroche C, Gitiaux C, Chretien F, Desguerre I, Mounier R, Chazaud B (2015) Skeletal muscle microvasculature: a highly dynamic lifeline. Physiology (Bethesda) 30:417–427
Lee Y, Kawagoe R, Sasai K, Li Y, Russell HR, Curran T, McKinnon PJ (2007) Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26:6442–6447
pubmed: 17452975
Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, Kikuchi Y, Takada I, Kato S, Kani S, Nishita M, Marumo K, Martin TJ, Minami Y, Takahashi N (2012) Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med 18:405–412
pubmed: 22344299
Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D, McMahon AP (2006) A novel somatic mouse model to survey tumorigenic potential applied to the hedgehog pathway. Cancer Res 66:10171–10178
pubmed: 17047082
pmcid: 3806052
Mravic M, Asatrian G, Soo C, Lugassy C, Barnhill RL, Dry SM, Peault B, James AW (2014) From pericytes to perivascular tumours: correlation between pathology, stem cell biology, and tissue engineering. Int Orthop 38:1819–1824
pubmed: 24566993
Ney JT, Fehm T, Juhasz-Boess I, Solomayer EF (2012) RANK, RANKL and OPG expression in breast cancer - influence on osseous metastasis. Geburtshilfe Frauenheilkd 72:385–391
pubmed: 25298541
pmcid: 4168338
Ono T, Hayashi M, Sasaki F, Nakashima T (2020) RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen 40:2
pubmed: 32047573
pmcid: 7006158
Raleigh DR, Reiter JF (2019) Misactivation of hedgehog signaling causes inherited and sporadic cancers. J Clin Invest 129:465–475
pubmed: 30707108
pmcid: 6355229
Rao S, Cronin SJF, Sigl V, Penninger JM (2018) RANKL and RANK: from mammalian physiology to cancer treatment. Trends Cell Biol 28:213–223
pubmed: 29241686
Raza A, Franklin MJ, Dudek AZ (2010) Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 85:593–598
pubmed: 20540157
Ribeiro AL, Okamoto OK (2015) Combined effects of pericytes in the tumor microenvironment. Stem Cells Int 2015:868475
Sato K, Lee JW, Sakamoto K, Iimura T, Kayamori K, Yasuda H, Shindoh M, Ito M, Omura K, Yamaguchi A (2013) RANKL synthesized by both stromal cells and cancer cells plays a crucial role in osteoclastic bone resorption induced by oral cancer. Am J Pathol 182:1890–1899
pubmed: 23499553
Shimo T, Matsumoto K, Takabatake K, Aoyama E, Takebe Y, Ibaragi S, Okui T, Kurio N, Takada H, Obata K, Pang P, Iwamoto M, Nagatsuka H, Sasaki A (2016) The role of sonic hedgehog signaling in osteoclastogenesis and jaw bone destruction. PLoS One 11:e0151731
Stratman AN, Malotte KM, Mahan RD, Davis MJ, Davis GE (2009) Pericyte recruitment during vasculogenic tube assembly stimulates endothelial basement membrane matrix formation. Blood 114:5091–5101
pubmed: 19822899
pmcid: 2788982
Tamayo-Orrego L, Charron F (2019) Recent advances in SHH medulloblastoma progression: tumor suppressor mechanisms and the tumor microenvironment. F1000Res 8:F1000 Faculty Rev-1823
Theunissen JW, de Sauvage FJ (2009) Paracrine hedgehog signaling in cancer. Cancer Res 69:6007–6010
pubmed: 19638582
Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, Unden AB (2006) Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol 208:17–25
pubmed: 16294371
Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22:2454–2472
pubmed: 18794343
Walsh MC, Choi Y (2021) Regulation of T cell-associated tissues and T cell activation by RANKL-RANK-OPG. J Bone Miner Metab 39:54–63
pubmed: 33438173
pmcid: 8670018
Wu X, Li F, Dang L, Liang C, Lu A, Zhang G (2020) RANKL/RANK system-based mechanism for breast cancer bone metastasis and related therapeutic strategies. Front Cell Dev Biol 8:76
pubmed: 32117996
pmcid: 7026132
Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ (1998) Activating smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90–92
pubmed: 9422511
Yamamoto M, Shook NA, Kanisicak O, Yamamoto S, Wosczyna MN, Camp JR, Goldhamer DJ (2009) A multifunctional reporter mouse line for Cre- and FLP-dependent lineage analysis. Genesis 47:107–114
pubmed: 19165827
pmcid: 8207679
Yasui R, Minatogawa T, Kanoh N, Nakata Y, Kubota A (2001) Nasal septal hemangiopericytoma-like tumor: a case report with an immunohistochemical study. Am J Rhinol 15:267–270
pubmed: 11554660
Zhang H, Wang Y, Chen T, Zhang Y, Xu R, Wang W, Cheng M, Chen Q (2019) Aberrant activation of hedgehog signalling promotes cell migration and invasion via matrix metalloproteinase -7 in ovarian cancer cells. J Cancer 10:990–1003
pubmed: 30854105
pmcid: 6400802
Zibat A, Missiaglia E, Rosenberger A, Pritchard-Jones K, Shipley J, Hahn H, Fulda S (2010) Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. Oncogene 29:6323–6330
pubmed: 20818440