Pancreatic stellate cell: Pandora's box for pancreatic disease biology

Table 1 Function of pancreatic stellate cells in the quiescent state and after activation

Physiological functions

Store fat and retinoids in their perinuclear droplets, expressing GFAP, desmin and vimentin

Secrete MMPs and TIMPs

Maintains ECM turnover

Involved in maintenance of pancreatic tissue architecture

No or limited secretion of cytokines, chemokines and growth factors

Function as an immune, progenitor and intermediary cell

Possible role in exocrine and endocrine secretions

Pathological functions

Exhibit cell proliferation and migration

Deranged ECM turnover due to loss of balance between MMPs and TIMPs

Secrete various cytokines, chemokines and growth factors and thereby contribute to inflammatory milieu

Stimulate cancer cell proliferation and migration and inhibit their apoptosis

Mediate invasion and metastasis of carcinoma cells

Mediate chemoresistance and radioresistance thereby promoting cancer cell survival

Contribute to the hypovascular and hypoxic tumour microenvironment

Promote angiogenesis, neural invasion and epithelial-mesenchymal transition

GFAP: Glial fibrillary acidic protein; MMPs: Matrix metalloproteinases; TIMPs: Tissue inhibitors of matrix metalloproteinases; NGF: Nerve growth factor.

Table 2 Therapeutic agents that have been used in experimental studies for inhibition of Pancreatic stellate cells in chronic pancreatitis

Ref	Agent	Class/type of agent	In vivo/in vitro (study) model	Outcome of the study
Nakamura et al[169] 2000	FOY-007 FOY-305	Synthetic serine protease inhibitor	Cytokine stimulated human periacinar fibroblast like cells	Both attenuated proliferation and procollagen type I C-terminal peptide (PIP)
				FOY-007 also inhibited collagen synthesis
Xie et al[170] 2002	IS-741	Carboxamide derivative	Wistar Bonn/Kobori rats	Suppressed the expression of IL-6 and CINC and pancreatic acute phase proteins (PAP and p8)
Kuno et al[171] 2003	Lisinopril	Angiotensin-converting enzyme (ACE) inhibitor	Wistar Bonn/Kobori rats	Increased pancreatic weight and decreased pancreatic MPO and serum ACE activity was observed
				Decrease in serum MCP-1 levels, intra-pancreatic hydroxyproline content was identified
				TGF-β1 mRNA overexpression was suppressed
Yamada et al[172] 2003	Candesartan	Angiotensin II receptor antagonist	Wistar Bonn/Kobori rats	Increased pancreatic weight and expression of angiotensinogen and angiotensin II receptor type 2 mRNA
				Decreased pancreatic MPO and serum ACE activity and hydroxyl proline content
				Suppressed TGF-β1 mRNA overexpression
Masamune et al[173] 2003	Y-27632 and HA-1077	Rho kinase inhibitors	Isolated PSCs from male Wistar rats	Inhibited α-SMA expression, proliferation, type I collagen production and chemotaxis
Nagashio et al[174] 2004	AdTb-ExR	Adenoviral vector system expressing TGF-β receptor	Caerulein induced CP in BALB/c mice	Reduced the activated PSCs, number of apoptotic acinar cells and fibrosis
				Weight of the pancreas increased
Zhao et al[175] 2005	Mutant MCP-1	…	DBTC induced CP in Lewis rats	Decreased MCP-1, fibrosis and hydroxyproline levels
				Reduced IL6, TGF-β, IL-1β, MCP-1 and PDGF expression
Gibo et al[176] 2005	Camostat mesilate	Oral protease inhibitor	In vivo: DBTC induced CP in Lewis rat In vitro: Culture activated PSCs	In vivo: Inflammation, fibrosis and cytokines expression was inhibited
				In vitro: PSC proliferation and MCP-1 production was reduced
Yamada et al[177] 2005	Lisinopril and candesartan	Angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker	Wistar Bonn/Kobori rats	Reduced MPO activity, hydroxyproline content, inflammation and fibrosis in combination therapy
				Suppressed mRNA expression of TGF-β1, PDGF- β and TNF-α
van Westerloo et al[178] 2005	Troglitazone	PPAR-γ ligand	Caerulein induced experimental CP in female C57BL6 mice	Intrapancreatic fibrosis and hydroxy proline contents were reduced
				Attenuated increase in MPO content and TGF-β1 levels
Reding et al[179] 2006	Rofecoxib	COX-2 inhibitor	Wistar Bonn/Kobori rats	Reduced TGF-β, collagen synthesis, inflammation and macrophage infiltration
Asaumi et al[180] 2006	Epigallocatechin-3-gallate EGCG	Antioxidant of polyphenols	Ethanol stimulated PSCs isolated from Wistar rats	Inhibited lipid peroxidation, SOD activity and p38 phosphorylation
				Decreased TGF-β1 and collagen secretion
Baumert et al[181] 2005 Fitzner et al[182] 2006	IFN-γ	Antifibrotic cytokine	Culture activated PSCs, isolated from LEW.1W rats and pancreatic stellate cell lines	Diminished PSC proliferation and collagen synthesis
				Inhibited α-SMA expression
				Induction of quiescent phenotype mediated through activated STAT1
Ohashi et al[183] 2006	Thioredoxin-1 (TRX-1)	Redox-regulating protein with antioxidative activity	Caerulein induced CP in wild type C57BL/6 mice and transgenic mice overexpressing TRX-1	Attenuated PSC activation and fibrosis
				TGF-β1 and PDGF expression was reduced
				Lower levels of MCP-1 in serum and acinar cells
McCarroll et al[184] 2006	Retinol and its metabolites	Vitamers of vitamin A	Ethanol stimulated culture activated rat PSCs	Inhibited PSC activation, proliferation, expression of collagen I. All MAP kinases were activated
Tasci et al[185] 2007	Allopurinol	Xanthine oxidase inhibitor	Trinitrobenzene sulfonic acid (TNBS) induced CP in Sprague-Dawley rats	PSC activation was inhibited in vivo
				Lower collagen deposition and lobular and sub-lobular atrophy was observed
Lu et al[186] 2007	Ascorbic acid	Antioxidant	DBTC induced CP in Sprague-Dawley rats	Decreased malondialdehyde (MDA), hyaluronic acid, laminin concentrations and pancreatic injury
				Increased superoxide dismutase activity
Shirahige et al[187] 2007	Taurine	Amino sulfonic acid	DBTC induced pancreatic fibrosis in Wistar rats Culture activated PSCs from Wistar rats	Improved pancreatic fibrosis in rats. Increased IL-6 and decreased IL-2 were observed in pancreatic tissue homogenates
				PSC culture supernatants showed decreased type I collagen, MMP-2 and TGF-β1
Rickmann et al[188]2007	Tocotrienols	Vitamin E family members	Culture activated PSCs isolated from Wistar rats	Reduced viability of activated PSCs by apoptosis and autophagy
Michalski CW et al[189] 2008	Canabinoid WIN 55,212-2	Aminoalkylindole derivative	Human PSCs from CP tissues	Reduced fibronectin, collagen1 and α-SMA levels
				Decreased IL-6, MCP-1 and MMP-2 secretion and invasiveness by PSCs
Weylandt et al[190] 2008	Omega-3 polyunsaturated fatty acids (n-3 PUFA )	Polyunsaturated fats	Caerulein-induced CP in fat-1 transgenic mice	Increased n-3 PUFA tissue levels
				Decreased PSC activation
				Less pancreatic fibrosis and collagen content
Karatas et al[191] 2008	Halofuginone	Synthetic halogenated derivative of febrifugine	Complete pancreatic duct obstruction and caerulein hyperstimulation in female Wistar rats	Lower serum amylase, lipase, hyaluronic acid, nitric oxide levels and tissue hydroxyproline levels
				Pancreatic inflammation and acinar cell atrophy was reduced
Fitzner et al[192] 2008	Bosentan	ET-1-receptor antagonist	Culture activated rat PSCs	Inhibited PSC proliferation and collagen synthesis
				Reduced the expression of ET-1, α-SMA and CTGF
Schwer et al[193] 2010	Carbon monoxide-releasing molecules-2 (CORMs)	Metal carbonyl compounds delivering carbon monoxide	Culture activated PSCs isolated from Wistar rats	PSC proliferation was inhibited through p38/HO-1 pathway activation
Nathan et al[194] 2010	Pancreatic secretory trypsin inhibitor (PSTI)		Caerulein induced CP in C57Bl/6 PSTI transgenic mice	Decreased MPO activity and inflammatory cell infiltration
				Reduction in collagen I and fibronectin mRNA levels
González et al[195] 2011	Palm oil tocotrienol-rich fraction	Vitamin E family members	Arginine induced chronic like pancreatitis in Wistar rats	Reduced amylase, hydroxyproline and TGF-β1 levels were observed
				Diminished α-SMA, fibronectin and collagen expression was identified
Long et al[196] 2011	Octreotide	Analog of somatostatin	In vivo: PSC induced Pancreas Graft Fibrosis in Rats (Sprague Dawley rats as donors and Wistar rats as recipients) In vitro: PSCs isolated from Sprague Dawley rats	In vivo: Reduced inflammatory cell infiltration and expression of α-SMA, collagen I and TGF-β1
				In vitro: PSC proliferation and activation was inhibited
Li et al[197] 2011	Pancreatic stone protein ⁄ regenerating protein	Secretory stress proteins family	Culture activated PSCs from human CP tissue obtained by outgrowth method	Inhibited PSC proliferation, migration and reduced. collagen I and fibronectin
				Increased MMP/TIMP ratio and promoted fibrolysis
Tang et al[198] 2011	Sinisan	Chinese herb	TNBS induced CP in Sprague-Dawley rats	Decreased serum amylase
				mRNA expression of TNF-α, IL-1β and COX-2 were reduced and IL-10 was increased
				α-SMA expression was reduced
Wei et al[199] 2011	Pravastatin	Competitive inhibitor of HMG-CoA	Pancreatic ductal hypertension induced CP in Wistar rats	Attenuated fibrosis and mRNA levels of TNF-α and TGF-β1 and increased IL-10 expression
				Exocrine secretion was improved
				SOD activity was increased
Li et al[200] 2011	α-Tocopherol	Vitamin E family member	TNBS induced CP in Sprague-Dawley rats	Reduced fibrosis and enhanced survival rate
				Pancreatic weight was increased in CP model
Monteiro et al[201] 2012	Vitamin E supplementation		Ethanol induced (alcoholic) CP in Wistar rats	mRNA levels of α-SMA, COX-2, IL-6, MIP-3α and TNF-α were decreased and PAP was increased
Matsushita et al[202] 2012	Taurine	Amino sulfonic acid	In vivo: DBTC induced CP in Wistar rats In vitro: AR42J acinar cells	Inhibited acinar cell apoptosis
Yang et al[203] 2012	L-Cysteine	Amino acid	In vivo: TNBS induced CP in Sprague-Dawley rats In vitro: Culture activated PSCs	Decreased α-SMA, TIMP-1, IL-1β TGF-β1 expression and hydroxylproline levels and increased MMP-2 levels
				Suppressed PSC proliferation and ECM synthesis
Bai et al[204] 2012	Sulindac	Non-steroidal anti-inflammatory drug	Caerulein induced CP in C57BL/6 mice	Reduced fibrosis, acinar cell loss and inflammatory cell infiltration
				TNF-α and MCP-1 levels were decreased
				Expression of TGF-β, PDGF-β, SHH and Gli was reduced
Lee et al[205] 2012	Simvastatin and Troglitazone	HMG-CoA reductase inhibitor and PPAR agonists	Culture activated PSCs isolated from Sprague-Dawley rats	PSC proliferation was inhibited synergistically
Shen et al[206] 2013	rCXCL9	Chemokine	In vivo: TNBS induced CP in Sprague-Dawley rats In vitro: Culture activated PSCs from Sprague-Dawley rats	In vivo: reduced fibrosis
				In vitro: protein expression of collagen 1α1 and TGF-β1 decreased
Gao et al[207] 2013	Bone morphogeneic proteins	TGF-β superfamily members,	In vivo: Caerulein induced CP in female Swiss Webster mice In vitro: PSCs isolated from female Swiss Webster mice and human pancreatic tissue	In vivo: BMP2 protein levels were increased
				In vitro: PSC pre-treatment with BMP2 attenuated TGF-β1, α-SMA, fibronectin and collagen type Iα expression
Zhou et al[208] 2013	Edaravone	Free radical scavenger	DBTC induced CP in Sprague-Dawley rats	Rats body weight was improved and reduced the fibrosis
				SOD activity was increased and MDA levels were decreased
				TGF-β, TNF-α and IL-6 levels were downregulated
				NF-κB and PSC activation was inhibited
Niina et al[209] 2014	ONO-1301	Prostacyclin agonist,	DBTC induced CP in Lewis rats	Reduced interstitial fibrosis and inflammatory cell infiltration
				Increased HGF and decreased IL-1β, TNF-α, TGF-β, MCP-1 and collagen mRNA expression was observed
Mrazek et al[210] 2015	Apigenin	Hydroxyflavone	In vivo: Caerulein induced pancreatitis in C57/BL6 mice In vitro: PSCs isolated from human pancreatic tissues	In vivo: Reduced pancreatic fibrosis and retained acinar cell morphology
				In vitro: Induced PSC apoptosis and death
				Downregulated the parathyroid hormone related protein induced fibronectin, collagen 1α1, PCNA, TGF-β and IL-6 expression
Tsang et al[211] 2015	Trans-resveratrol	Natural stilbenoid	Rat pancreatic stellate cell line LTC-14	Collagen type I, α-SMA and fibronectin was downregulated both at mRNA and protein level
				NF-κB activation was decreased
Lin et al[212] 2015	Rhein, Emodin, and Curcumin	Phenolic compounds	Rat pancreatic stellate cell line LTC-14	Collagen type I, α-SMA and fibronectin expression was decreased
Gundewar et al[213] 2015	L49H37	Curcumin analog	Immortalized human pancreatic stellate cell line	Inhibited PSC proliferation and promoted apoptosis
				Decreased the phosphorylation of ERK1/2
Tsang et al[214] 2015	Eruberin A	Flavanol glycoside	Rat PSC line LTC-14	Inhibited expression of α-SMA Collagen type I and fibronectin. Reduced the activation of NF-κB and phosphorylation PI3K/AKT
Bläuer et al[215] 2015	1,25-dihydroxyvitamin D3	Vitamin D metabolite	PSCs isolated from C57BL6JOlaHsd mouse	Antiproliferative and antifibrotic effects were observed
Xiao et al[216] 2015	Retinoic acid	Vitamin A Metabolite	In vivo: Caerulein induced CP in Balb/c mice In vitro: Culture activated PSCs	Decreased expression of TGF-βRII, collagen 1α1 PDGF-Rβ and β-catenin
				Nuclear translation of β-catenin was decreased
				Wnt 2 and β-catenin protein expression was downregulated
				Inhibited PSC proliferation and induced apoptosis
Witteck et al[217] 2015	Trametinib and dactolisib	MEK inhibitor and PI3kinase/mTOR inhibitor	Culture activated PSCs isolated from Lewis rats	Both drugs inhibited PSC proliferation
				Trametinib suppressed the expression of IL-6 and TGF-β1
				Dactolisib decreased the levels of α-SMA and Collagen type Iα1
Ulmasov et al[218] 2016	CWHM-12 (RGD peptidomimetic compound)	Integrin inhibitor	In vivo: Caerulein induced pancreatitis in C57/BL6 mice In vitro: Rat PSC line LTC-14	Pancreatic fibrosis, acinar cell atrophy and loss was reduced
				Decreased the expression of TGF-β regulated genes and PSC activation

CINC: Cytokine-induced neutrophil chemoattractant-1; MCP-1: Monocyte chemoattractant protein-1; DBTC: Dibutyltin dichloride; MPO: Myeloperoxidase; PSC: Pancreatic stellate cell; CP: Chronic pancreatitis; α-SMA: α-smooth muscle actin; PDGF: Platelet derived growth factor; TGF-β: Transforming growth factor-β; COX-2: Cyclooxygenase-2; MAP: Mitogen activated protein; CTGF: Connective tissue growth factor; SOD: Superoxide dismutase; TNBS: Trinitrobenzene sulfonic acid; MMP: Matrix metalloproteinase; MDA: Malondialdehyde; HMG-CoA: 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; TNF-α: tumor necrosis factor-α; IL: Interleukin; SHH: Sonic hedgehog; MIP: Macrophage inflammatory protein-3; NF-κB: Nuclear factor-κB; HGF: Hepatocyte growth factor; PCNA: Proliferating cell nuclear antigen.

Table 3 Therapeutic agents that have been evaluated in experimental/pre-clinical studies targeting pancreatic stellate cells and cancer stroma in pancreatic ductal adenocarcinoma

Ref	Agent	Class/type of agent	In vivo/in vitro (study) model	Outcome of the study
Feldmann et al[219] 2007	Cyclopamine	Steroidal alkaloid	Orthotopic xenograft model	Inhibited cancer cell invasion and metastasis by suppressing hedgehog
Diep et al[220] 2011	Erlotinib RDEA119 and AZD6244	EGFR tyrosine Kinase and MAP kinase inhibitors	In vitro: Pancreatic cancer cell lines In vivo: BxPC-3 and MIA PaCa-2 mice xenograft model	Inhibited cancer cell proliferation, EGF receptor signaling and induced apoptosis
				Suppressed tumour growth
Froeling et al[221] 2011	ATRA, 9-cis-RA and 13-cis-RA	Metabolites of vitamin A	In vivo: LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice In vitro: AsPc1 and Capan1 pancreatic cancer cell lines, PS1 and other PSC cell lines	Retinoic acid induced PSC quiescence and decreased migration
				Decreased and induced proliferation and apoptosis of cancer cells
Chauhan et al[222] 2013	Losartan	Angiotensin inhibitor	Orthotopic mice model	Reduced stromal collagen production, expression of TGF-β1, CCN2 and ET-1
				Improved drug and oxygen delivery to tumour
Sun et al[223] 2013	Curcumin	Phenolic compound	TGF-β1 stimulated PANC-1 cell line	Inhibited proliferation and promoted apoptosis
				Cancer cell invasion and migration was decreased
Edderkaoui et al[224] 2013	Ellagic acid Embelin	Polyphenolic and benzoquinone phytochemical	Pancreatic cancer cells and PSCs	Induced apoptosis and inhibited proliferation
				NF-κB activity was decreased
Macha et al[225] 2013	Guggulsterone	Plant polyphenol	CD18/HPAF and Capan1 cell clones	Inhibited growth and colony formation
				Induced apoptosis and arrested cell cycle
				Decreased motility and invasion
Kozono et al[226] 2013	Pirfenidone	Pyridone compound	In vivo: Orthotopic tumour mice Model In vitro: PSCs isolated from pancreatic tissue	In vivo: Reduced tumour growth, PSC proliferation and the deposition of collagen type I and periostin in tumours was decreased
				In vitro: Proliferation, invasiveness and migration of PSCs was inhibited
Guan et al[227] 2014	Retinoic acid	Vitamin A derivative	Panc-1 and Aspc-1 cell lines Cancer associated fibroblasts	Reduced α-SMA, FAP and IL-6 expression
				Inhibited cancer cell migration and EMT
Gonzalez-Villasana et al[228] 2014	Bisphosphonates and nab-paclitaxel	Monocyte-macrophage lineage inhibitors	In vitro: Human PSCs and cancer cell line In vivo: Orthotopic mice model	In vitro: Inhibited PSC activation, proliferation MCP-1 release and collagen 1 expression and induced apoptosis
				In vivo: Reduced tumour size, fibrosis, proliferation and increased apoptosis
Pomianowska et al[229] 2014	Prostaglandin E2 (PGE2)	Lipid compound	Human PSCs isolated from resected pancreatic tumour tissue	IL-1β and EGF induced COX-2 expression, TGF-β induced collagen synthesis and PDGF induced PSC proliferation was inhibited
Gong et al[230] 2014	Nexrutine	Phytoceutical with COX-2 Inhibitor activity	In vitro: pancreatic cancer cell lines In vivo: BK5-COX-2 transgenic mice	In vitro: promoted cancer cell apoptosis and reduced their growth
				Suppressed COX-2 expression
				In vivo: NF-κB and Stat3 activity and fibrosis was decreased
Yan et al[231] 2014	Crizotinib	c-MET/HGF receptor and ALK tyrosine kinases inhibitor	In vitro: Human pancreatic cancer cell lines AsPC-1, PANC-1, MIA PaCa-2 and Capan-1 In vivo: Mouse xenograft model	In vitro: Growth and proliferation was inhibited
				Induced apoptosis
				Inhibited ALK activity
				In vivo: Inhibited angiogenesis, tumour growth and ALK activity
Zhang et al[232] 2014	5-Azacytidine	Cytidine analogue	Bxpc-3 cancer cell line	Inhibited cancer cell proliferation by suppressing Wnt/β-catenin signaling
Wang et al[233] 2014	miR-216a	microRNA	In vitro: Capan-2 and PANC-1 pancreatic cancer cell lines In vivo: BALB/c nude mice	In vitro: Inhibited cell growth and induced apoptosis
				Down regulated survivin and XIAP expression
				In vivo: Inhibited xenograft tumour growth by suppressing JAK2/STAT3 signaling pathway
Kumar et al[234] 2015	miR-let7b and GDC-0449	microRNA and Hedgehog inhibitor	In vitro: Capan-1, HPAF-II, T3M4 and MIA PaCa-2 cell lines In vivo: Athymic nude mice bearing ectopic tumour	In vitro: Decreased cell proliferation and induced apoptosis via Gli dependent mechanism
				In vivo: Reduced tumour cell proliferation with increased apoptosis and tumour growth was inhibited
Petrova et al[235] 2015	RU-SKI 43	Hedgehog acyltransferase inhibitor	In vitro: Pancreatic cancer cell lines In vivo: Panc-1 xenograft mouse model	In vitro: Reduced cancer cell proliferation and Gli-1 activation through Smo independent signaling
				Decreased Akt and mTOR activity
				In vivo: Tumour growth decreased
Massó-Vallés et al[236] 2015	Ibrutinib	Tyrosine kinase inhibitor	Transgenic mouse and xenograft mice models	Reduced fibrosis and extended survival
Zhou et al[237] 2015	Zileuton	5-LOX inhibitor	Pancreatic cancer SW1990 cell line	Induced apoptosis, decreased proliferation and expression of 5-lipoxygenase
Lui et al[238] 2015	Desferrioxamine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and Di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone	Thiosemicarbazones	In vitro: PANC-1 and MIAPaCa-2 In vivo: PANC-1 tumour xenograft mice	Activation of the non-receptor tyrosine kinase Src and cAbl was decreased in vitro and STAT3 activation was reduced in both in vivo and in vitro condition
Khan et al[239] 2015	Ormeloxifene	Nonsteroidal drug	Pancreatic cancer cell lines and PDAC xenograft mice	Inhibited cell proliferation, tumour stroma through SHH pathway and stromal cell infiltration
				Decreased collagen I expression
				Restored the tumour-suppressor miR-132 expression
Liu et al[240] 2016	Oridonin	Tetracycline diterpenoid compound	Aspc1, Bxpc3, Panc1 and SW1990 cell lines	Migration and EMT was inhibited by affecting Wnt/β-catenin signal events
Haqq et al[241] 2016	Gemcitabine with omega-3 polyunsaturated fatty acid emulsion, (LipidemTM)	Nucleoside analog	In vitro studies using pancreatic cancer cell lines Capan-1 and Panc-1 and PSC cell line; RLT-PSC	Drugs showed antiproliferative and anti-invasive effects
Ji et al[242] 2016	MMP2 responsive liposome loaded with Pirfenidone and gemcitabine	---	In vivo: BALB/c nude Orthotopic tumour mice model In vitro: Human PSCs isolated from surgical specimens of Pancreatic cancer	Pirfenidone inhibited collagen I and TGF-β expression in PSCs
				Gemcitabine killed pancreatic tumour cells

PSC: Pancreatic stellate cell; TGF-β: Transforming growth factor-β; CCN2: Connective tissue growth factor; NF-κB: Nuclear factor-κB; FAP: Fibroblast activation protein; EMT: Epithelial-mesenchymal transition; MCP-1: Monocyte chemoattractant protein-1; COX-2: Cyclooxygenase-2; PDAC: Pancreatic ductal adenocarcinoma; SHH: Sonic hedgehog; PDGF: Platelet derived growth factor; ALK: Anaplastic lymphoma kinase; MMP: Matrix metalloproteinase; XIAP: X-linked inhibitor of apoptosis protein; IL: Interleukin; HGF: Hepatocyte growth factor; mTOR: Mechanistic target of rapamycin.