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Pancreatic Stellate Cells (PSC) 87

PSC

Figure9.1 (a) Expression of the cytoskeletal protein desmin in pancreatic stellate cells (PSC): a representative photomicrograph of a

normal rat pancreatic section immunostained for the stellate cell selective marker desmin is shown on the left with a corresponding line diagram on the right. Desmincells. (b) PSC in early culture exhibiting a typical flattened polygonal shape. The nucleus is surrounded by numerous vitamin A- containing lipid droplets in the cytoplasm. Source: Apte et al. (1998) / Reproduced with permission from BMJ Publishing Group Ltd.

positive (brown) PSC with long cytoplasmic projections can be seen along the basolateral aspects of acinar

fibronectin, and laminin, but also the enzymes (matrix metalloproteinases [MMP] and their inhibitors [TIMP]) that degrade ECM [10]. Evidence has now emerged to indicate that PSC may serve several other functions in the healthy pancreas, including (i) a role in innate immunity and first- line defense (since they express toll- like receptors, TLR 2, 3, 4, and 5 [11], which recognize PAMPs, DAMPs, and alarmins), as well as their ability to phagocytose cell debris and neutrophils[12]; (ii) as mediators of cholecystokinin- induced pancreatic enzyme secretion (since they respond to CCK via CCK receptors by secreting acetylcholine), which in turn acts on muscarinic receptors on acinar cells to stimulate enzyme secretion[13]; and (iii) progenitor- like capabilities since they express several stem cell markers, including CD133, SOX9, nestin, and GDF3[14,15]. They can differentiate into other cell types including insulin- secreting cells under the influence of relevant growth factors.

PSC inDisease

During pancreatic injury, PSC are activated, i.e., they transform from their quiescent state to a myofibroblastlike phenotype characterized by loss of vitamin A stores, expression of alpha smooth muscle actin (αSMA), fibroblast activation protein (FAP), fibroblast specific protein (FSP1), and fibrinogen [16] (Table 9.1). Activated PSC synthesize and secrete excessive amounts of ECM proteins, overwhelming their ability to degrade these proteins, eventually causing fibrosis of the gland. PSC can be

Table9.1 Characteristics ofquiescent andactivated pancreatic

stellate cells (PSC).

Characteristic Quiescent PSC Activated PSC

Vitamin A lipidcontaining droplets

Alpha smooth muscle actin

Proliferation Basic Enhanced Ability to migrate No Yes Collagen production Limited Increased Activity of matrix

metalloproteinases (MMP) and tissue inhibitors of matrix proteinases (TIMP)

Cytokine production

Ability for phagocytosis

Protein expression Basal

Abundant Absent

Not expressed

In equilibrium

Limited Increased

No Present

expression

Expressed

TIMP > MMP

inflammatory cytokines (PDGF, TGFβ, CTGF, IL-

1, IL- 6, IL- 15)

(CD6- mediated) Differential

expression

activated by a wide range of factors, each of which is pertinent to pancreatic pathophysiology either as a factor that is upregulated/modulated during pancreatic disease

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Table9.2 Factors causing pancreatic stellate cell activation.

Angiotensin Cyclooxygenase 2 (COXEndothelinEndotoxin Ethanol and its metabolites (acetaldehyde, fatty acid ethyl

esters) Fibrinogen GalectinHyperglycemia Hypoxia Inflammatory mediators (cytokines, growth factors,

complement) Lipopolysaccharide Nicotine Oxidant stress Parathyroid hormonePigment epitheliumProteases

related protein (PTHrP)

derived factor

or as a compound that is directly injurious to the gland (listed in Table 9.2). Notably, in addition to being activated by exogenous cytokines (released by surrounding acinar or inflammatory cells) via paracrine routes, PSC are capable of producing their own cytokines, which act on the cells via corresponding receptors (autocrine pathways) resulting in a state of perpetual activation thus further facilitating pathological fibrosis.

Signaling pathways that mediate activation of PSC are being increasingly identified (summarized in Table 9.3). Furthermore, close interactions between several of these pathways have now been characterized, implying that there is considerable redundancy when it comes to modulation of PSC activation [17–20]. Interestingly, several studies have shown that a number of the above signaling pathways converge to a common downstream mediator of PSC activation, namely a sustained increase in intracellular calcium[21]. In recent years, attention has been focused on microRNA, (small noncoding RNA) in PSC because they are now recognized as important factors in numerous cell functions including proliferation, differentiation, apoptosis, and protein synthesis. Several miRNA have been showntobe differentially expressed between quiescent and activated PSC [22]. MicroRNA 15b and 16 (reported to regulate PSC apoptosis)[23] and miR21 are postulated to be cofactors in connective tissue growth factor (CCN2)mediated PSC activation[24]. MicroRNA are often transported by small extracellular vesicle (exosomes) secreted by a variety of cell types. A recent study has shown that exosomes from acinar cells carrying miR- 130a- 3p can fuse

Table9.3 Signaling pathways involved inpancreatic stellate cell

(PSC) activation.

Factor Pathway involved Outcome

Oxidative stress Nrf2 antioxidant

Nicotine α7nAChR-

LPS NLR family pyrin

TGF-

β1 SNHG/miR- 34b/

siRNA Notch3 Inhibits the activation,

222740 Rho/MRTF

CCG-

Tissue injury/ pathogens

Ethanol and growth factors

Thiazolidinediones PPR γpathway PSC activation

IL- 6 JAK2/ STAT3

siRNA transcription

pathway

mediated JAK2/ STAT3 signaling pathway

domaincontaining 3inflammasome

LIF pathway

pathway

Sonic hedgehog/ Smo/Gli pathway

MAPK pathway PSC activation and

pathway

factor NF-

κBpathway

PSC activation and pancreatic fibrosis

PSC activation, proliferation, αexpression, and ECM formation

Activation of PSC

Proliferation, migration, and ECM accumulation

proliferation, and migration of cancer cells

Reduces PSC activation and modulates immune cells

PSC activation and perineural invasion

fibrosis

inhibition PSC activation and

immune modulation PSC activation,

proliferation, apoptosis

SMA

with PSC membranes, with consequent transport of miR130a into PSC where it binds to and inhibits PPARγ leading to PSC activation[25]. In addition to the identification of factors causing PSC activation, in recent times attention has been turned toward signaling pathways and factors that maintain PSC quiescence or reverse activated PSC to their quiescent state. These are discussed in more detail in the context of development of therapeutic approaches to inhibit/reverse pancreatic fibrosis under thesection titled “Reversal of Pancreatic Fibrosis.”

Over the past decades several major advances have been made in our understanding of the role of PSC in the diseased pancreas. It is clear that PSC are critical to the process of regeneration and repair in acute pancreatitis (usually a self- limiting inflammatory condition), but also play a central role in disease progression in recurrent acute and chronic pancreatitis as well as pancreatic cancer.

Acute Pancreatitis (AP)

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In the majority of cases, acute pancreatitis is a self- limiting condition, with restitution of pancreatic structure and function to normal within a few weeks. Early in the disease process and in response to acinar cell- derived trypsin[26] as well as the chemokines/cytokines released by damaged acinar cells and the infiltrating inflammatory cells, PSC become activated and proliferate rapidly. While most of the increased PSC numbers comprise proliferating resident cells, a small proportion (7–18%) are derived from circulating bone marrow cells [9]. Activated PSC are thought to play a role in the progression of AP via synthesis of nitric oxide, which in turn further damages acinar cells[26,27]. However, they also play a major role in recovery from AP. The ECM proteins produced by these activated PSC provide a supportive lattice and a scaffold that supports the regeneration of acinar and ductal cells during recovery from acute pancreatitis. Notably, the ECM regulates the critical integrin-

mediated interactions between cell membranes and the surrounding matrix, which in turn are important controllers of cell proliferation and differentiation. In the absence of integrin receptors (as demonstrated by studies using β1- integrin knockout mice[28], ECM synthesis by PSC is inhibited. This is associated with increased apoptosis and decreased proliferation of acinar cells, thereby delaying the process of pancreatic repair.

PSC also play an important role in aiding regeneration and remodeling after severe necrotizing acute pancreatitis. In a seminal study using pancreatic tissue from patients with severe acute pancreatitis, Zimmerman et al. [29] found outgrowth of “pilot ductules” from islands of granulation tissue (comprised of remnant acini, ductules, and stellate cells). These ductules exhibited a mantle of stellate cells which are thought to support growth and differentiation of ductal cells into mature duct and acinar cells. Thus, PSC may be critical to the reconstitution of pancreatic parenchymal cells after acute injury. Additionally, the MMPs and TIMPs secreted by the cells may help in the remodeling process by removal of excess ECM via fibrinolysis, while activated PSC are removed through processes such as apoptosis, senescence and/or reversion to quiescence.

Chronic Pancreatitis (CP)

Chronic necroinflammation of the pancreas (chronic pancreatitis) is characterized histologically by abundant fibrosis that surrounds islands of atrophied acini and distorted pancreatic ducts. Notably, fibrosis is also detected within and around pancreatic islets despite the absence of obvious necroinflammation of the islet cells[30]. Studies involving dual staining for collagen and the PSC activation

Chronic Pancreatitis (CP) 89

Figure9.2 Activated pancreatic stellate cells (PSC) in chronic

pancreatitis: a section from a patient with chronic pancreatitis showing colocalization of staining for the PSC activation marker alpha smooth muscle actin (αSMA, brown) and collagen using Sirius Red (red) (dual staining) in fibrotic areas of the pancreas. Source: Haber et al. (1999) / Reproduced with permission of Elsevier.

marker αSMA (using Sirius Red stain and immunohistochemistry, respectively) combined with immunostaining for selective PSC markers have conclusively demonstrated the presence of activated PSC in fibrotic areas (Fig. 9.2) around acini and ducts as well as around islets; more importantly, dual staining for αSMA and procollagen mRNA has established that activated PSC are the predominant source of collagen I in the fibrotic pancreas[31]. As with AP, the increased numbers of PSC in CP are sourced mainly from the resident PSC population, with a small proportion being derived from pluripotent circulating bone marrow cells [32]. Interestingly, activated PSC are known to cause beta- cell dysfunction (decreased insulin secretion and apoptosis), and these effects are further aggravated by hyperglycemia[33]. These findings indicate that PSC- mediated islet cell dysfunction may be a factor in the diabetes of chronic pancreatitis.

The role of PSC in CP has been studied using human

CP tissue (which usually only allows point-

in- time assessments) and experimental models of CP (which allow examination of chronological events during fibrosis development and progression). Space restrictions preclude a detailed discussion of the current (predominantly rodent) models of CP noted in Table9.4. Each model has its advantages and deficiencies, but possibly the most physiologically relevant model (particularly for alcoholic chronic pancreatitis) involves chronic ethanol administration followed by endotoxin challenge (given the welldemonstrated increase in serum endotoxin levels in heavy drinkers)[34]. With the recent focus on the role of smoking in chronic pancreatitis and the knowledge that smoking aggravates alcoholic CP, models have been developed whereby alcohol- fed, endotoxin challenged rats or mice

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Table9.4 Rodent models ofchronic pancreatitis.

Repeated injections of caerulein Pancreaticobiliary duct ligation Intraductal injection of trinitrobenzene sulfonic acid (TNBS) Tail vein injection of dibutyltin chloride (DBTC) Chronic alcohol administration with additional challenge/

intervention

● Pancreatic duct ligation

● Free fatty acids

● Caerulein

● Endotoxin/LPS

● Smoke exposure

are exposed to tobacco smoke[35]. These studies support the concept that smoke exposure significantly increases the severity and progression of alcohol- induced pancreatic injury and fibrosis.

Mechanistic insights gained from the above work indicate that during CP, PSC are activated by numerous factors/pathways including (i) the profibrogenic growth factor TGFβ, which is found to be highly expressed in spindle- shaped cells and in infiltrating M2 macrophages within fibrotic areas and also in acinar cells adjacent to areas of fibrosis (but not in acinar cells away from fibrotic areas), supporting the notion that TGFβ induces PSC activation via paracrine and autocrine pathways [31]; (ii) platelet- derived growth factor (PDGF) acting via the PDGF receptor known to be upregulated in fibrotic areas, thereby providing a possible mechanism for the observed increase in proliferation and migration of PSC to injured areas during pancreatic necroinflammation [31]; (iii) nerve growth factor (NGF), demonstrated to be expressed in PSC in areas of fibrosis, and implicated in the pain of chronic pancreatitis via its ability to induce neurite growth[36]; (iv) oxidative stress, as evidenced by increased staining of oxidant stress marker 4- hydroxynonenal[37]; (v) cigarette smoke compounds (via activation of the α7nicotinic acetylcholine receptor [α7NACh receptor]) expressed on PSC [35]. Notably, a positive feed- forward loop is set up between PSC and macrophages, whereby the interleukins IL4 and IL13 produced by activated PSC promote further transformation of macrophages to the M2 phenotype, which, in turn secrete IL22, TGFβ, and PDGF to cause further PSC activation and progression of fibrosis[38].

Reversal ofPancreatic Fibrosis

Our improved understanding of the biology of PSC and their role in the fibrosis of chronic pancreatitis has led to a dramatic increase in efforts in the field to develop

targeted therapies to prevent/inhibit/retard the fibrogenic process. It must be acknowledged, however, that the efficacy of most approaches has largely only been demonstrated in animal models and translation of these findings to clinical settings is awaited. The potentially useful strategies suggested by pre- clinical studies are itemized in Table9.5 and include:

1) Modulation of growth factors: Inhibition or degrada-

tion of profibrogenic growth factors TGFβ and tumor necrosis factor alpha (TNFα) and their downstream signaling [38–43], histone deacytylase (HDAC) inhibitor[44], heat shock protein (HSP90) inhibitor[45].

2) Antioxidants: Vitamin E [46], ellagic acid, a plant

polyphenol [47], salvianolic acid, a herbal medicine [48]; and irisin, an exercise- induced hormone[49], N- acetylcysteine[50].

3) Protease inhibitors[51].

4) Modulation of signaling pathways: Troglitazone and

miR- 130a- 3p binding to the peroxisome proliferator receptor gamma, PPARγ [12,25]; retinoic acid-

Table9.5 Reversal ofpancreatic fibrosis.

Mechanism Compounds

Modulation of growth factors

Antioxidants Vitamin E, ellagic acid, salvianolic acid,

Protease inhibitors

Modulation of signaling pathways

Inhibition of collagen synthesis

Antiinflammatory approach

Behavioral modification

Plant compounds Rhein, apigenin, curcumin, saikosponin

Vitamins Vitamin D– isoforms D2 and D3, vitamin

Induction of quiescence of activated PSC

Inhibitors of TGFβ, TNFα, HDAC, HSP90

irisin, N- acetylcysteine Camostat mesylate, dasatinib, CP734

Troglitazone and miR- 130a- 3p binding to PPARγ; Retinoic acid– Wnt–catenin pathway; miR- 200a –TGF- β1/PTEN/Akt/ mTOR pathway; 3- methyladenine (3- MA)– PI3K pathway

Collagen siRNA

Prostacyclin analogue ONO- 1301; amygdalin; indomethacin; isoliquiritigenin

Alcohol withdrawal

A, date palm fruit extract

A (retinol) or its metabolites such as retinoic acid

Melatonin, bone morphogenic protein, troglitazone, kinase inhibitors– sorafenib, sunitinib, trametinib, dactolisib, and dasatanib, coenzyme Q10

Pancreatic Cancer 91

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induced PSC quiescence via suppression of the Wnt– catenin pathway[52]; miR- 200a- mediated inhibition of TGF- β1- induced PSC activation and extracellular matrix formation through inhibition of the PTEN/ Akt/mTOR pathway[53]; 3- methyladenine (3- MA), a PI3K inhibitor causing decreased fibrosis by decreasing autophagy in PSC[54].

5) Inhibition of collagen synthesis: Collagen siRNA[55].

6) Anti- inflammatory approach: A prostacyclin ana-

logue ONO- 1301, which inhibits proinflammatory and profibrogenic cytokine production[56]; amygdalin, which inhibits PSC activation and attenuates fibrosis by decreasing production of profibrotic cytokines in a rat CP model induced by injecting dibutyltin dichloride (DBTC)[57]; inhibition of cyclooxygenase by indomethacin, an anti- inflammatory drug that results in decreased activation of PSC[58]; isoliquiritigenin, a component of licorice which decreases macrophage infiltration and attenuates caerulein- induced pancreatic fibrosis[59].

7) Behavioral modification: Alcohol withdrawal in

alcohol- induced pancreatitis[60].

8) Plant compounds exerting a range of effects that

inhibit PSC activation: An anthraquinone derivative rhein and a flavonoid, apigenin; curcumin (a polyphenol found in turmeric) reported to inhibit activation of PSC through the inhibition of IL1β, which decreases TNFα- induced activation of activator protein- 1 (AP- 1) and mitogen- activated protein (MAP) kinases (ERK, c- Jun N- terminal kinase [JNK], and p38MAP kinase)[61]; conophylline, a plant alkaloid, which decreases fibrosis through the inhibition of ERK1/2in PSC[62]; resveratrol, a natural polyphenol, which decreases oxidative stress- induced activation and glycolysis in PSC, mediated by ROS/ miR- 21[63]; genestein, a natural isoflavone, which decreases fibrosis in human PSC transfected with let- 7d to express thrombospondin 1, a marker of fibrosis[64]; saikosponin A, the active component of the Chinese medicine chaihu, which decreases PSC activation, viability, proliferation, and migration, and promotes apoptosis by inhibiting autophagy and the formation of NLRP3inflammasome via the AMPK/ mTOR pathway[65]; date palm fruit extract, which decreases fibronectin-

1 and αSMA, markers of fibro-

sis in PSC activated by TNF- α[66].

9) Vitamin D and its isoforms D2 and D3 decrease

in vitro PSC activation by decreasing IL- 6 [67]. Notably, in vivo studies with the vitamin D ligand calcipotriol have shown significant attenuation of the fibrosis of chronic pancreatitis in mice [68]. Based on these findings, a clinical trial is under way (NCT02965898, Laukkarinen J, Tampere University Hospital) to assess if vitamin D supplementation can

prevent progression of recurrent AP to chronic pancreatitis. Since storage of vitamin A is associated with PSC quiescence, administration of vitamin A (retinol) or its metabolites such as retinoic acid, has been assessed in models of chronic pancreatitis. In this regard, vitamin A-

containing liposomes combined with TLR4- silencing shRNA has been reported to inhibit pancreatic fibrosis in mouse models of chronic pancreatitis [69]. Interestingly, vitamin A deficiency was seen to promote islet stellate cell activation and dysregulation of glucose metabolism in mice, an effect that was mitigated by supplementation of vitamin A[70].

10) Induction of quiescence of activated PSC: Melatonin, the

anthraquinone derivative rhein [71], bone morphogenic protein[72], troglitazone (a ligand for the peroxisome proliferator activated receptor PPARγ) [25,73]; kinase inhibitors (sorafenib, sunitinib, trametinib, dactolisib, and dasatanib), which have been shown to inhibit PSC proliferation and ECM synthesis[74–76]. Interestingly, trametinib also decreases the expression of two autocrine mediators of PSC activation, IL6 and TGFβ[75]. Coenzyme Q10 suppresses PSC activation by inhibiting autophagy through PI3K/ATK/mTOR signaling[77].

Pancreatic Cancer

It is now well established that the abundant collagenous stroma of pancreatic cancer is produced predominantly by PSC (discussed in more detail below). It is also increasingly clear that PSC play a much wider role to aid cancer progression via active crosstalk not only with cancer cells but also with other stromal cells. Consequently, the development of novel approaches to interrupt this crosstalk is considered a critical addition to currently available treatment strategies for pancreatic cancer.

The fibrotic stroma of pancreatic cancer comprises extracellular matrix proteins including collagen type I, fibronectin, and laminin, noncollagenous factors such as glycosaminoglycans (e.g., hyaluronan), glycoproteins, and proteoglycans, and several cell types, including stellate cells, endothelial cells, neural elements, and immune cells[78].

Studies with human pancreatic cancer sections, involving dual staining for PSChybridization for collagen mRNA, have established that PSC are the major source of the fibrosis of pancreatic cancer[79] (Fig.9.3). Activated PSC have been identified surrounding the earliest (premalignant) lesions of pancreatic cancer, such as pancreatic intraepithelial neoplasms (PanIN) and intraductal papillary mucous

selective markers and in situ

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Figure9.3 Low- and high- power views of a human pancreatic cancer section dual stained for alpha smooth muscle actin (αSMA) and

collagen mRNA: immunostaining for αSMA (brown) combined with in situ hybridization for collagen mRNA (blue) reveals colocalization of the two stains in stromal areas of the section with no staining in tumor cells. This pattern of staining indicates that pancreatic stellate cells are the main source of collagen in pancreatic cancer stroma. Source: Apte et al. (2004) / Reproduced with permission from Wolters Kluwer Health.

neoplasms (IPMN), indicating that PSC activation is an early feature in carcinogenesis[80,81]. While PSC may act to restrain early- stage cancer growth, it is now widely accepted that eventually cancer cells subvert PSC function to their own benefit[82,83]. Indeed, a positive correlation has been reported between the extent of activated PSC in the stroma and poor clinical outcome as assessed by overall survival[84,85].

Recent studies have prompted a recognition of the significant inter- and intra- tumoral heterogeneity exhibited by PSC in pancreatic cancer tissue. Ikenaga and colleagues[86] first reported identifying two populations of PSC based on positive or negative staining for the membrane metalloproteinase CD10, with patients with CD10+ve PSC exhibiting worse outcomes. Subsequently, subtypes of cancer- associated fibroblasts (CAFs) were described by Ohlund etal.[87]— those at a distance from neoplastic cells showing an inflammatory phenotype (high expression of interleukin 6 [IL6] and relatively low expression of αSMA), termed inflammatory CAF or iCAF; and those adjacent to malignant cells showing a myofibroblastic phenotype (high αSMA expression) termed myofibroblastic CAF or myCAF[87]. Since then, a study by Neuzillet etal.[88] using transcriptomic analyses, has reported the presence of four subtypes of CAF (A, B, C, and D) in pancreatic cancer. Each of these subtypes demonstrates specific functional and molecular features and appears to exert different effects on disease prognosis. The authors found that PSC exhibited features mainly of subtypes B and C (prominent expression of myosin II and podoplanin, respectively).

As noted earlier, the role of PSC in pancreatic cancer extends well beyond merely producing the fibrotic

stroma. Using invitro (cocultured PSC and cancer cells) and in vivo (subcutaneous xenografts, orthotopic implants, genetically engineered models) approaches, a close bidirectional interaction between PSC and cancer cells has been identified, which facilitates local tumor growth and distant metastasis[82,89]. Pancreatic cancer cells induce PSC activation, as evidenced by increased proliferation, ECM production, and migration. In turn, PSC significantly increase pancreatic cancer cell proliferation, while at the same time inhibiting their apoptosis, thereby increasing cancer cell survival. PSC also stimulate cancer cell migration (an effect associated with enhanced epithelial–mesenchymal transition [EMT]) and stemness of cancer cells. Interestingly, cancer cells have been found to induce autophagy in PSC leading to release of alanine, which acts as an alternative carbon source for the TCA cycle and lipid synthesis in cancer cells, thus improving cancer cell survival in the nutrientpoor and hypoxic environment of PDAC [90]. The transport of alanine between PSC and cancer cells is reported to be mediated by the SLC1A4 transporter, which is upregulated on cancer cells and may serve as a novel therapeutic target to inhibit cancer cell metabolism [91]. The factors/signaling pathways that mediate the interactions of PSC and cancer cells are being increasingly elucidated. A detailed discussion of these is out of the scope of this chapter, but the major factors aresummarized in Table9.6. Interactions of PSC with other cells in the tumor microenvironment are covered in Chapter 123.

A known characteristic of pancreatic desmoplasia is its ability to interfere with the delivery of chemotherapeutic agents to cancer cells. Hessmann et al. [92] demonstrate that PSC/cancer- associated fibroblasts are not only resistant

Table9.6 Signaling pathways mediating interactions between pancreatic stellate cells andcancer cells.

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Mediator Signaling pathway Functional role

Pancreatic Cancer 93

PSC- derived CXCL12 (SDF- 1)

PSC- derived SDF- 1 Galectin- 1 Proliferation of PSC and chemokine production

Smo, Gli Hedgehog pathway PSC activation, ECM synthesis, migration, desmoplasia,

HGF HGF/c- MET pathway PSC promote proliferation and metastasis of tumor cells CCL2 Hypoxia inducible factor 1

IL-

6 IL6/JAK/STAT PSC activation and proliferation

Kindlin-

2 Integrin Cytokines production in PSC facilitating progression

MAPK Mitogen-

Periostin Periostin pathway Periostin secreted by PSC promoting PCC proliferation,

γ ligands Peroxisome proliferator-

PPAR-

PDGF PI3Hyperglycemia Protein kinase C PSC proliferation, α-

Suppression of miRNA-

associated protein kinase Rho- ROCK pathway Activation of PSC, collagen I synthesis, and fibrosis

RhoSMAD-

2,3 SMADS PSC activation, proliferation, ECM deposition,

TLR9 Toll-

Vitamin D Vitamin D receptor PSC quiescence; decreased chemoresistance

catenin Wnt/β- catenin signaling Invasion of PCCs

βCaveolin-

NGF PI3K/AKT/GSK signal pathway Cancer cell proliferation and invasion

1 (Cav- 1) Cav- 1- ROS signaling Promotes tumor growth and induces stroma–tumor

21 Reactive oxygen species (ROS) PSC activation and induction of glycolysis

CXCL12 (SDFsignaling

(HIF-

(MAPK) signaling pathway

activated gamma (PPARγ)

Kinase pathway PSC migration and proliferation

like receptor (TLR)

signaling

activated protein kinase

Immunosuppression

facilitating PCC metastasis

angiogenesis; PCC proliferation, migration, and chemoresistance

PSC activation, Macrophage recruitment

and migration of PCC PSC proliferation, TIMP- 1 production

EMT, and resistance to nutrient deprivation and hypoxia Inhibition of PSC activation, proliferation, and collagen

synthesis Increased phagocytosis

SMA, collagen- I production,

angiogenesis

transdifferentiation, TGF- β1 expression Immunosuppression; PSC- derived cytokine production

metabolic coupling

α- SMA: alpha smooth muscle actin; c- MET: tyrosine- protein kinase of Met; CCL: chemokine ligand; CXCL: chemotactic cytokine ligand; ECM: extracellular matrix; JAK/STAT: Janus kinase/signal transducers and activators of transcription; HGF: hepatocyte growth factor; NGF: nerve growth factor; PCC: pancreatic cancer cells; PDGF: platelet- derived growth factor; PSC: pancreatic stellate cells; SDF: stromal- derived factor; SMAD: small worm mothers against decapentaplegic.

to gemcitabine themselves but can convert gemcitabine into an inactive metabolite 2′,2′- difluorodeoxyuridine thus decreasing the availability of active agent to destroy tumor cells. PSC may also directly modulate the response of cancer cells to chemotherapeutic agents. In an autocrine response to stromal- derived factor 1α (SDF- 1α) secreted by PSC, the cells secrete IL6, which in turn exerts a protective effect on cancer cells from the apoptotic effect of gemcitabine [93]. In addition, post- chemotherapy, PSC may

facilitate proliferation of residual cancer stem cells leading to recurrence[94].

In view of the emerging strong evidence of the importance of the microenvironment to pancreatic cancer outcomes, there is general agreement in the field that targeting cancer cells alone will remain an inadequate treatment approach and that modulating the microenvironment in addition to chemotherapy represents an essential element of future novel therapies. New high- throughput screening

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modalities have the potential to allow faster identification of potentially useful compounds that target stromal– tumor interactions[95].

Conclusion

In summary, it is now unequivocally established that the cells responsible for fibrogenesis in the pancreas are pancreatic stellate cells (PSC). In health, PSC maintain a fine balance between ECM production and degradation, thereby ensuring normal ECM turnover in the gland. PSC may also have additional roles in the healthy pancreas as progenitor cells, immune cells, and intermediary cells in CCK- regulated pancreatic exocrine secretion. In diseased states, PSC are transformed into an activated myofibroblastECM proteins. When the activation of PSC is limited, as in resolving acute pancreatitis, PSC can aid the regenerative/repair process. However, perpetuated activation of the cells, as seen in chronic pancreatitis and pancreatic cancer, ultimately leads to pathologic fibrosis. Notably, it

like state, producing excessive amounts of

is now becoming increasingly evident that PSC have functions beyond the fibrotic process in both chronic pancreatitis and pancreatic cancer. In chronic pancreatitis, PSC have been shown to facilitate acinar cell injury, interact with M2 macrophages and to promote islet (beta) cell dysfunction. In pancreatic cancer, PSC display heterogeneity facilitating both inflammation and fibrosis and they interact closely with cancer cells and other stromal cells such as endothelial cells, immune cells, nerve cells as well as the ECM itself to influence cancer progression. Understanding the biology of these multifunctional PSC will underpin the development of novel therapeutic approaches for difficult-

to- treat fibrotic diseases of the pancreas such as chronic pancreatitis and pancreatic cancer.

Acknowledgment

The authors gratefully acknowledge the assistance of Jakir Hossain and Alpharaj Mekapogu in collating references for this chapter.

References

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shaped cells in rat pancreas: identification, isolation, and culture. Gut 1998;43(1):128–133.

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