Carlo Pincelli
e-mail: carlo.pincelli AT unimore.it
website: www.pincelliskinlab.unimore.it
affiliation: Università di Modena-Reggio Emilia
research area(s): Cell Biology, Cancer Biology
Course:
Molecular and Regenerative Medicine
University/Istitution: Università di Modena-Reggio Emilia
University/Istitution: Università di Modena-Reggio Emilia
Carlo Pincelli earned his M.D. and the Specialization in Dermatology from the University of Modena and Reggio Emilia. He worked as Clinical Assistant Dermatologist at the Dermatology Clinic of the University of Modena and Reggio Emilia and at St. John’s Hospital for Diseases of the Skin in London. He was trained at research institutions internationally (Department of Dermatology, University of California in San Francisco and School of Medicine at Boston University, Boston). From 1998, is Associate Professor at the Department of Dermatology, University of Modena and Reggio Emilia. From 2005, is Chair of Clinical Applications of Medical Biotechnologies: Cutaneous Diseases, in the School of Biosciences and Biotechnologies and from 2006, he is Faculty member and has a teaching position at PhD School in Molecular and Regenerative Medicine at the University of Modena and Reggio Emilia.
Since 1995, CP is the Head of the Laboratory of Cutaneous Biology at the Department of Medicine and Medical Specialties, University of Modena and Reggio Emilia.
CP has been Associate Editor of the Journal of Investigative Dermatology (1999-2002), and, since 2005, he is Associate Editor of Experimental Dermatology. He has been in the Board of the European Society for Dermatological Research (2003-2008), and has served as the president of the ESDR in 2006-2007. Since 2007, Carlo is member of the International Psoriasis Council, and, since 2008, he is member of the Board of Trustees of the European Skin Research Foundation. Since 2009, he is member of the Scientific Committee of Eporgen Venture.
CP has published over 150 articles in international peer-reviewed journals with particular contributions in areas such as stem cell, molecular and cell biology, apoptosis and dermatology
ROLE OF INTEGRINS IN KERATINOCYTES APOPTOSIS Integrins are a major family of transmembrane glicoproteins that act as adhesion molecules and mediate survival in human keratinocytes. Loss of adhesion of keratinocytes induces a special type of apoptosis called anoikis. Our lab studies anoikis mechanisms; in particular we focus on the role of beta1-integrin and its splice variants. We will study anoikis pathways both in normal human skin and in hyperproliferative diseases, such as psoriasis and Squamous Cell Carcinoma (SCC).
ROLE OF P75NTR IN HUMAN KERATINOCYTES P75NTR is the neurotrophins (NTs) low affinity receptor. It is a transmembrane receptor and belongs to the TNF-receptor superfamily. P75NTR has controversial roles: when expressed with Trks, the NTs high affinity receptors, it acts as a co-receptor and increases Trks’ affinity for NTs, mediating survival; when alone, it can induce apoptosis in different cellular systems, with an unknown mechanism. We demonstrated that NTs mediate survival in human keratinocytes when p75NTR binds to Trks. We therefore want to study the role of p75NTR in this system in order to confirm its double function: mediator of survivor if acts as a co-receptor, inducer of apoptosis if alone.
ROLE OF NEUROTROPHINS AND THEIR RECEPTORS IN MALIGNANT MELANOMA NTs consist of a family of proteins able to bind two classes of transmembrane receptors: the high affinity receptors Trks and the low affinity receptor p75NTR. Interactions between these proteins constitute a network highly studied in many cellular systems. We analyzed their expression and function in melanoma cell lines and we found that they have an important role in melanoma proliferation and migration. Melanoma cells are resistant to chemotherapy-induced apoptosis. We studied the pro-apoptotic role of p75NTR in apoptosis induced by chemiotherapeutic agents. We are now analyzing and designing new peptides able to induce apoptosis by binding p75NTR in melanoma cells, in order to overcome melanoma chemioresistance.
ROLE OF FAS LIGAND IN THE PATHOGENESIS OF PEMPHIGUS Pemphigus is an auto-immune skin disease, characterized by the presence of auto-antibody anti-desmoglein in sera of pemphigus patients. This phenomena leads to the loss of adhesion of suprabasal keratinocytes and blister formation. Pemphigus is a chronic lethal disease controlled by high doses steroids. We demonstrated that pemphigus sera contains high levels of Fas Ligand; they return to physiologic levels after corticosteroid treatment. We observed that high levels of Fas Ligand as well as pemphigus sera induce apoptosis in cultured human keratinocytes. We are now working to obtain a molecule able to inhibit Fas Ligand action in order to replace chronic steroid therapy.
CHARACTERIZATION OF KERATINOCYTE STEM CELL NICHE Keratinocyte Stem Cells (KSC) are responsible for epidermal renewal and need to be protected and clustered in their “niche”, the microenvironment that surrounds them and regulates their proliferation and differentiation. The niche is a combination of soluble factors and cell-cell interactions maintained to ensure protection to the resident cells, with both a functional and structural role. Among these factors, survivin, beta1-integrin, neurotrophins and their receptors, Notch and CD44 are differently expressed by keratinocytes and dermal fibroblasts. We therefore want to study the involvement of these molecules in KSC niche and their expression during skin ageing and upon UV irradiation.
ROLE OF NEUROTROPHINS IN THE SKIN Neurotrophins (NTs) are a family of structurally correlated proteins, which includes NGF, BDNF, NT-3 and NT-4, and acts through the high affinity receptors TrkA, TrkB and TrkC and the low affinity recptor p75NTR. It was previously demonstrated that NTs create a complex network in skin and regulate skin homeostasis. Fibroblasts are the main cellular type of the dermal compartment and are responsible for extracellular matrix components production and the maintaining of epidermal integrity by differentiation into myofibroblasts. NGF promotes dermal fibroblast differentiation into myofibroblasts, by inducing a-SMA expression. We therefore want to study the expression and function of NTs and their receptors in dermal fibroblasts.
ROLE OF P75NTR IN HUMAN KERATINOCYTES P75NTR is the neurotrophins (NTs) low affinity receptor. It is a transmembrane receptor and belongs to the TNF-receptor superfamily. P75NTR has controversial roles: when expressed with Trks, the NTs high affinity receptors, it acts as a co-receptor and increases Trks’ affinity for NTs, mediating survival; when alone, it can induce apoptosis in different cellular systems, with an unknown mechanism. We demonstrated that NTs mediate survival in human keratinocytes when p75NTR binds to Trks. We therefore want to study the role of p75NTR in this system in order to confirm its double function: mediator of survivor if acts as a co-receptor, inducer of apoptosis if alone.
ROLE OF NEUROTROPHINS AND THEIR RECEPTORS IN MALIGNANT MELANOMA NTs consist of a family of proteins able to bind two classes of transmembrane receptors: the high affinity receptors Trks and the low affinity receptor p75NTR. Interactions between these proteins constitute a network highly studied in many cellular systems. We analyzed their expression and function in melanoma cell lines and we found that they have an important role in melanoma proliferation and migration. Melanoma cells are resistant to chemotherapy-induced apoptosis. We studied the pro-apoptotic role of p75NTR in apoptosis induced by chemiotherapeutic agents. We are now analyzing and designing new peptides able to induce apoptosis by binding p75NTR in melanoma cells, in order to overcome melanoma chemioresistance.
ROLE OF FAS LIGAND IN THE PATHOGENESIS OF PEMPHIGUS Pemphigus is an auto-immune skin disease, characterized by the presence of auto-antibody anti-desmoglein in sera of pemphigus patients. This phenomena leads to the loss of adhesion of suprabasal keratinocytes and blister formation. Pemphigus is a chronic lethal disease controlled by high doses steroids. We demonstrated that pemphigus sera contains high levels of Fas Ligand; they return to physiologic levels after corticosteroid treatment. We observed that high levels of Fas Ligand as well as pemphigus sera induce apoptosis in cultured human keratinocytes. We are now working to obtain a molecule able to inhibit Fas Ligand action in order to replace chronic steroid therapy.
CHARACTERIZATION OF KERATINOCYTE STEM CELL NICHE Keratinocyte Stem Cells (KSC) are responsible for epidermal renewal and need to be protected and clustered in their “niche”, the microenvironment that surrounds them and regulates their proliferation and differentiation. The niche is a combination of soluble factors and cell-cell interactions maintained to ensure protection to the resident cells, with both a functional and structural role. Among these factors, survivin, beta1-integrin, neurotrophins and their receptors, Notch and CD44 are differently expressed by keratinocytes and dermal fibroblasts. We therefore want to study the involvement of these molecules in KSC niche and their expression during skin ageing and upon UV irradiation.
ROLE OF NEUROTROPHINS IN THE SKIN Neurotrophins (NTs) are a family of structurally correlated proteins, which includes NGF, BDNF, NT-3 and NT-4, and acts through the high affinity receptors TrkA, TrkB and TrkC and the low affinity recptor p75NTR. It was previously demonstrated that NTs create a complex network in skin and regulate skin homeostasis. Fibroblasts are the main cellular type of the dermal compartment and are responsible for extracellular matrix components production and the maintaining of epidermal integrity by differentiation into myofibroblasts. NGF promotes dermal fibroblast differentiation into myofibroblasts, by inducing a-SMA expression. We therefore want to study the expression and function of NTs and their receptors in dermal fibroblasts.
1. Palazzo E, Marconi A, Truzzi F, Dallaglio K, Petrachi T, Humbert P, Schnebert S, Perrier E, Dumas M, Pincelli C. (2011). Role of neurotrophins on dermal fibroblast survival and differentiation. J Cell Physiol. Apr 18 epub
2. Truzzi F, Marconi A, Atzei P, Panza MC, Lotti R, Dallaglio K, Tiberio R, Palazzo E, Vaschieri C, Pincelli C. (2011) p75 neurotrophin receptor mediates apoptosis in transit-amplifying cells and its overexpression restores cell death in psoriatic keratinocytes. Cell Death Differ Jun18: 948-958
3. Truzzi F, Marconi A, Pincelli C. (2011) Neurotrophins in healthy and diseased skin. Dermatoendocrinol. Jan; 3(1):32-6
4. van de Kerkhof P, Barker J, Griffiths CE, Menter A, Leonardi C, Young M, Kemeny L, Pincelli C, Bachelez HX, Katsambas A, St X00e5 Hle M, Horn EJ, Sterry W. (2010) Improving clinical trial design in psoriasis: Perspectives from the global dermatology community. J Dermatolog Treat. Oct 1.
5. Lotti R, Marconi A, Truzzi F, Dallaglio K, Gemelli C, Borroni RG, Palazzo E, Pincelli C. (2010) A previously unreported function of Beta(1)B integrin isoform in caspase-8-dependent integrin-mediated keratinocyte death. J Invest Dermatol. Nov;130(11):2569-77.
6. Pincelli C, Marconi A. Keratinocyte stem cells: friends and foes.(2010) J Cell Physiol. Nov;225(2):310-5.
7. Borroni RG, Truzzi F, Pincelli C. The skin neurotrophic network in health and disease.(2009) Actas Dermosifiliogr. Dec;100 Suppl 2:70-4.
8. Pincelli C, Lotti R. What's new in laboratory research? (2009) J Rheumatol Suppl. Aug;83:17-8.
9. Grando SA, Bystryn JC, Chernyavsky AI, Frusiç-Zlotkin M, Gniadecki R, Lotti R, Milner Y, Pittelkow MR, Pincelli C. (2009) Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis. Exp Dermatol. Sep;18(9):764-70.
10. Pincelli C, Pignatti M, Borroni RG. ( 2009 ) Pharmacogenomics in dermatology: from susceptibility genes to personalized therapy. Exp Dermatol.Apr;18(4):337-49.
11. Dallaglio K, Palazzo E, Marconi A, Dumas M, Truzzi F, Lotti R, Bontè F, Pincelli C. (2009) Endogenous survivin modulates survival and proliferation in UVB-treated human keratinocytes. Exp Dermatol. May;18(5):464-71
12. Marconi A, Panza MC, Bonnet-Duquennoy M, Lazou K, Kurfurst R, Truzzi F, Lotti R, De Santis G, Dumas M, Bonté F, Pincelli C. (2006) Expression and function of neurotrophins and their receptors in human melanocytes. Int J Cosmet Sci. Aug;28(4):255-61.
13. Truzzi F, Marconi A, Lotti R, Dallaglio K, French LE, Hempstead BL, Pincelli C. (2008) Neurotrophins and Their Receptors Stimulate Melanoma Cell Proliferation and Migration. J Invest Dermatol. 128:2031-2040
14. Fantini F, Greco A, Cesinaro AM, Surrenti T, Peris K, Vaschieri C, Marconi A, Giannetti A, Pincelli C. (2008) Pathologic changes after photodynamic therapy for Basal cell carcinoma and Bowen disease: a histologic and immunohistochemical investigation. Arch Dermatol. 144(2):186-94.
15. Chirico F, Fumelli C, Marconi A, Tinari A, Straface E, Malorni W, Pellicciari R, Pincelli C. Carboxyfullerenes localize within mitochondria and prevent the UVB-induced intrinsic apoptotic pathway. Exp Dermatol. 2007. 16(5):429-36.
16. Peters EM, Raap U, Welker P, Tanaka A, Matsuda H, Pavlovic-Masnicosa S, Hendrix S, Pincelli C. Neurotrophins act as neuroendocrine regulators of skin homeostasis in health and disease. Horm Metab Res. 2007. 39(2):110-24.
17. Marconi A, Dallaglio K, Lotti R, Vaschieri C, Truzzi F, Fantini F, Pincelli C. (2007) Survivin identifies keratinocyte stem cells and is downregulated by anti-beta1 integrin during anoikis. Stem Cells. . 25(1):149-55.
18. Marconi A, Panza MC, Bonnet-Duquennoy M, Lazou K, Kurfurst R, Truzzi F, Lotti R, De Santis G, Dumas M, Bonté F, Pincelli C. Expression and function of neurotrophins and their receptors in human melanocytes. Int J Cosmet Sci. 2006. 28(4):255-61.
19. Pincelli C, Henninger E, Casset-Semanaz F. The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab. Arch Dermatol Res. 2006. 298(7):329-38.
20. "Amagai M, Ahmed AR, Kitajima Y, Bystryn JC, Milner Y, Gniadecki R, Hertl M, Pincelli C, Kurzen H, Fridkis-Hareli M, Aoyama Y, Frusić-Zlotkin M, Müller E, David M, Mimouni D, Vind-Kezunovic D, Michel B, Mahoney M, Grando S. Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just ""witnesses of disease""? Exp Dermatol. 2006. 15(10):815-31.
21. Botchkarev VA, Yaar M, Peters EM, Raychaudhuri SP, Botchkareva NV, Marconi A, Raychaudhuri SK, Paus R, Pincelli C. Neurotrophins in skin biology and pathology. J Invest Dermatol. 2006. 126(8):1719-27.
2. Truzzi F, Marconi A, Atzei P, Panza MC, Lotti R, Dallaglio K, Tiberio R, Palazzo E, Vaschieri C, Pincelli C. (2011) p75 neurotrophin receptor mediates apoptosis in transit-amplifying cells and its overexpression restores cell death in psoriatic keratinocytes. Cell Death Differ Jun18: 948-958
3. Truzzi F, Marconi A, Pincelli C. (2011) Neurotrophins in healthy and diseased skin. Dermatoendocrinol. Jan; 3(1):32-6
4. van de Kerkhof P, Barker J, Griffiths CE, Menter A, Leonardi C, Young M, Kemeny L, Pincelli C, Bachelez HX, Katsambas A, St X00e5 Hle M, Horn EJ, Sterry W. (2010) Improving clinical trial design in psoriasis: Perspectives from the global dermatology community. J Dermatolog Treat. Oct 1.
5. Lotti R, Marconi A, Truzzi F, Dallaglio K, Gemelli C, Borroni RG, Palazzo E, Pincelli C. (2010) A previously unreported function of Beta(1)B integrin isoform in caspase-8-dependent integrin-mediated keratinocyte death. J Invest Dermatol. Nov;130(11):2569-77.
6. Pincelli C, Marconi A. Keratinocyte stem cells: friends and foes.(2010) J Cell Physiol. Nov;225(2):310-5.
7. Borroni RG, Truzzi F, Pincelli C. The skin neurotrophic network in health and disease.(2009) Actas Dermosifiliogr. Dec;100 Suppl 2:70-4.
8. Pincelli C, Lotti R. What's new in laboratory research? (2009) J Rheumatol Suppl. Aug;83:17-8.
9. Grando SA, Bystryn JC, Chernyavsky AI, Frusiç-Zlotkin M, Gniadecki R, Lotti R, Milner Y, Pittelkow MR, Pincelli C. (2009) Apoptolysis: a novel mechanism of skin blistering in pemphigus vulgaris linking the apoptotic pathways to basal cell shrinkage and suprabasal acantholysis. Exp Dermatol. Sep;18(9):764-70.
10. Pincelli C, Pignatti M, Borroni RG. ( 2009 ) Pharmacogenomics in dermatology: from susceptibility genes to personalized therapy. Exp Dermatol.Apr;18(4):337-49.
11. Dallaglio K, Palazzo E, Marconi A, Dumas M, Truzzi F, Lotti R, Bontè F, Pincelli C. (2009) Endogenous survivin modulates survival and proliferation in UVB-treated human keratinocytes. Exp Dermatol. May;18(5):464-71
12. Marconi A, Panza MC, Bonnet-Duquennoy M, Lazou K, Kurfurst R, Truzzi F, Lotti R, De Santis G, Dumas M, Bonté F, Pincelli C. (2006) Expression and function of neurotrophins and their receptors in human melanocytes. Int J Cosmet Sci. Aug;28(4):255-61.
13. Truzzi F, Marconi A, Lotti R, Dallaglio K, French LE, Hempstead BL, Pincelli C. (2008) Neurotrophins and Their Receptors Stimulate Melanoma Cell Proliferation and Migration. J Invest Dermatol. 128:2031-2040
14. Fantini F, Greco A, Cesinaro AM, Surrenti T, Peris K, Vaschieri C, Marconi A, Giannetti A, Pincelli C. (2008) Pathologic changes after photodynamic therapy for Basal cell carcinoma and Bowen disease: a histologic and immunohistochemical investigation. Arch Dermatol. 144(2):186-94.
15. Chirico F, Fumelli C, Marconi A, Tinari A, Straface E, Malorni W, Pellicciari R, Pincelli C. Carboxyfullerenes localize within mitochondria and prevent the UVB-induced intrinsic apoptotic pathway. Exp Dermatol. 2007. 16(5):429-36.
16. Peters EM, Raap U, Welker P, Tanaka A, Matsuda H, Pavlovic-Masnicosa S, Hendrix S, Pincelli C. Neurotrophins act as neuroendocrine regulators of skin homeostasis in health and disease. Horm Metab Res. 2007. 39(2):110-24.
17. Marconi A, Dallaglio K, Lotti R, Vaschieri C, Truzzi F, Fantini F, Pincelli C. (2007) Survivin identifies keratinocyte stem cells and is downregulated by anti-beta1 integrin during anoikis. Stem Cells. . 25(1):149-55.
18. Marconi A, Panza MC, Bonnet-Duquennoy M, Lazou K, Kurfurst R, Truzzi F, Lotti R, De Santis G, Dumas M, Bonté F, Pincelli C. Expression and function of neurotrophins and their receptors in human melanocytes. Int J Cosmet Sci. 2006. 28(4):255-61.
19. Pincelli C, Henninger E, Casset-Semanaz F. The incidence of arthropathy adverse events in efalizumab-treated patients is low and similar to placebo and does not increase with long-term treatment: pooled analysis of data from Phase III clinical trials of efalizumab. Arch Dermatol Res. 2006. 298(7):329-38.
20. "Amagai M, Ahmed AR, Kitajima Y, Bystryn JC, Milner Y, Gniadecki R, Hertl M, Pincelli C, Kurzen H, Fridkis-Hareli M, Aoyama Y, Frusić-Zlotkin M, Müller E, David M, Mimouni D, Vind-Kezunovic D, Michel B, Mahoney M, Grando S. Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just ""witnesses of disease""? Exp Dermatol. 2006. 15(10):815-31.
21. Botchkarev VA, Yaar M, Peters EM, Raychaudhuri SP, Botchkareva NV, Marconi A, Raychaudhuri SK, Paus R, Pincelli C. Neurotrophins in skin biology and pathology. J Invest Dermatol. 2006. 126(8):1719-27.
Project Title:
Keratinocyte Stem Cells and Skin Carcinogenesis: The Role of Survivin
Epidermis is the outermost layer of the skin and is continuously renewed by a subpopulation of stem keratinocytes (KSC) that account for around 10% of the cells in the basal compartment. KSC are able to self renew and to generate transit amplifying (TA) cells that undergo terminal differentiation after few rounds of division. KSC reside in a microenvironment named niche and, unlike the more differentiated TA cells, are protected from apoptosis because of the highest levels of β1-integrin, which allows the adhesion to the extracellular matrix, and of a number of anti-apoptotic factors (Tiberio et al., FEBS Lett 31;524:139-44 2002). We have shown previously that survivin, a member of the inhibitor of apoptosis protein family (IAP), is almost exclusively expressed in KSC (Chiodino et al., J Invest Dermatol 113:415-8 1999). Survivin is present in different cell pools, namely at the nuclear and cytoplasmic level. Survivin subcellular expression seems to be related to different functions, although data are still controversial (Colnaghi et al., J Biol Chem 281:33450-6 2006). We have reported that survivin is mostly expressed in the nucleus of KSC and in the cytoplasm of TA cells, which seems to be consistent with their different rate of proliferation in vitro (Marconi et al., Stem Cells 25:149-55 2007). Moreover, survivin knock-down increases keratinocyte susceptibility to type B ultraviolet radiations (UVB)-induced apoptosis (Dallaglio et al., Exp Dermatol 18:464-71 2009). UVB radiation is the most important inducing factor in skin cancer formation. Non-melanoma skin cancers (NMSC) include squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), both originating from malignant transformation of keratinocytes. While in BCC metastasis is a rare event, SCC exhibits a significant propensity to metastasize. UVB induce DNA mutations in human epidermal keratinocytes, particularly targeting the p53 gene. Upon UVB radiation, DNA can either be repaired or, if the system fails, keratinocyte expressing wild-type p53 are eliminated via apoptosis. On the contrary, keratinocyte carrying p53 mutations undergo malignant transformation, resulting in cancer formation. Survivin cooperates with loss of functional p53, counteracting UVB-induced apoptosis (Grossman et al., J Clin Invest 108:991-9 2001). Moreover, survivin expression in mouse skin promotes papilloma conversion to SCC (Allen et al., Cancer Res 63:567-72 2003). Survivin expression is increased in human SCC as compared to healthy skin (Lo Muzio et al., Exp Mol Pathol 70:249-54 2001). KSC have been largely considered the origin of NMSC. Indeed, not only they are protected from apoptosis, but their long life span favors the accumulation of an increasing number of mutations (Morris et al., Cancer Res 46:3061-6 1986). Recently, to better clarify the role of KSC in skin carcinogenesis, several studies have attempted to isolate and characterize stem cells in cancer. The cancer stem cell hypothesis suggests that not only stem cells may be able to generate cancer, but also to sustain the tumor once it has formed (Bonnet and Dick, Nat Med 3:730-71997). Moreover, the putative stem cell population would account for cancer recurrence and resistance to therapy. Recently, CD133 has been identified as a marker for cancer stem cells isolation (Curley at al., Stem Cells 27:2875-83 2009). Moreover, data suggest that CD133, a transmembrane protein with still unknown functions, is a possible marker for human SCC stem cells (Society for Investigative Dermatology Meeting in Montreal, 2009; J Invest Dermatol Suppl abstract 155).
The aim of this project will be to evaluate the role of survivin in KSC in relation to SCC, with regard to both skin carcinogenesis and cancer maintenance.
The aim of this project will be to evaluate the role of survivin in KSC in relation to SCC, with regard to both skin carcinogenesis and cancer maintenance.