Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Nicole Lintern
 -- 3693 2023-08-31 10:50:56 |
2 references update
Fanny Huang
 Meta information modification 3693 2023-09-01 08:36:03 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Lintern, N.M.; Smith, A.M.; Jayne, D.G.; Khaled, Y.S. Pancreatic Ductal Adenocarcinoma Stroma in Photodynamic Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/48681 (accessed on 05 August 2024).
Lintern NM, Smith AM, Jayne DG, Khaled YS. Pancreatic Ductal Adenocarcinoma Stroma in Photodynamic Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/48681. Accessed August 05, 2024.
Lintern, Nicole M., Andrew M. Smith, David G. Jayne, Yazan S. Khaled. "Pancreatic Ductal Adenocarcinoma Stroma in Photodynamic Therapy" Encyclopedia, https://encyclopedia.pub/entry/48681 (accessed August 05, 2024).
Lintern, N.M., Smith, A.M., Jayne, D.G., & Khaled, Y.S. (2023, August 31). Pancreatic Ductal Adenocarcinoma Stroma in Photodynamic Therapy. In Encyclopedia. https://encyclopedia.pub/entry/48681
Lintern, Nicole M., et al. "Pancreatic Ductal Adenocarcinoma Stroma in Photodynamic Therapy." Encyclopedia. Web. 31 August, 2023.
Pancreatic Ductal Adenocarcinoma Stroma in Photodynamic Therapy
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers15164135

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid malignancies, with a five-year survival of less than 10%. The resistance of the disease and the associated lack of therapeutic response is attributed primarily to its dense, fibrotic stroma, which acts as a barrier to drug perfusion and permits tumour survival and invasion. As clinical trials of chemotherapy (CT), radiotherapy (RT), and targeted agents have not been successful, improving the survival rate in unresectable PDAC remains an urgent clinical need. Photodynamic stromal depletion (PSD) is a recent approach that uses visible or near-infrared light to destroy the desmoplastic tissue. Preclinical evidence suggests this can resensitise tumour cells to subsequent therapies whilst averting the tumorigenic effects of tumour–stromal cell interactions. So far, the pre-clinical studies have suggested that photodynamic therapy (PDT) can successfully mediate the destruction of various stromal elements without increasing the aggressiveness of the tumour. 

pancreatic ductal adenocarcinoma photodynamic therapy stroma tumour microenvironment

 1. Introduction

Pancreatic cancer was responsible for 466,000 deaths worldwide in 2020; yet, the total number of cases diagnosed was only marginally greater (496,000) [1]. It is the seventh leading cause of cancer death across the sexes [1], though projections show it will rise to third place by 2025 [2]. This is in part due to the lack of biomarkers and imaging tools for early detection; it is also due to its aggressiveness [3]. Pancreatic ductal adenocarcinoma (PDAC) accounts for 85–95% of all solid pancreatic tumours [4] and usually originates in the exocrine cells of the pancreatic ducts. One of the most distinct features of PDAC is its high stromal content, which can constitute 90% of the tumour [5]. The complex interplay between stromal components and cancer cells permits both disease initiation and progression, including metastasis to other organs [6][7]. The greatest challenge in PDAC treatment is the continued production and deposition of a fibrous extracellular matrix (ECM), which is refractory to most interventions including chemo- and immunotherapies [8]. The dense tissue gives rise to a hypovascular tumour with elevated interstitial fluid pressure (IFP), resulting in difficulties in drug delivery and distribution [9]. Because of this, resistance to current therapies remains a major challenge.
Given that surgical resection with radical intent remains the only curative approach in the clinical management of pancreatic cancer [10], the state of disease at diagnosis is classified as resectable, borderline resectable (BR), or non-resectable (locally advanced or metastatic) according to strict criteria [11][12][13]. Treatment commences accordingly (Figure 1).
Figure 1. An outline of the standard treatment pathways for pancreatic ductal adenocarcinoma. At initial presentation, just 15–20% of patients are suitable for upfront resection. Adjuvant CT (AC) is the standard of care (SOC) following resection in PDAC. A greater proportion of patients present with borderline resectable (BR) disease (20–30%) and typically receive neoadjuvant CT (NACT) before surgical evaluation. Half of patients present with initially non-resectable (NR) disease, though if locally advanced (LA) surgical evaluation will be considered following NACT. As there is little evidence supporting surgical resection for metastatic PDAC, palliative CT is adopted. CT: chemotherapy.
A pancreaticoduodenectomy (Whipple) or distal pancreatectomy is the most commonly performed first-line treatment for PDAC [14]. Whilst these surgeries can increase long-term survival, they infrequently achieve R0 resection and negatively impact on quality of life. Without any additional therapies, 60–80% of patients relapse within the first year [15][16][17]. Combined with the fact that just 10–20% of patients are suitable for resection at diagnosis [18], most cases require a multi-modal treatment strategy. Surgical resection followed by adjuvant CT is the standard approach for resectable PDAC following years of clinical trials suggesting its benefit to overall and disease-free survival (DFS) [19][20][21]. The standardised regimens include gemcitabine (Gem), a nucleoside analogue, or FOLFIRINOX (FFX), a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin. The latter is more effective, with one study showing a 3-year DFS of 39.7% vs. 21.4% with Gem [21]. However, 30–40% of patients fail to receive adjuvant chemotherapy due to postoperative complications [22][23][24] or early disease progression [25][26]. Of those that do begin postoperative chemotherapy, many fail to complete the course due to toxicity and decrease in performance status [27][28]. Ultimately, 60–75% of patients receiving FFX and other chemotherapies soon relapse [29][30][31][32], with the median overall survival (OS) following surgical resection and CT being ~20–40 months [33][34][35].
Due to the inadequacy of this approach, neoadjuvant chemotherapy (NAT) has recently been implemented for PDAC, mostly in the BR and locally advanced (LA) settings [36]. NAT can downstage advanced tumours to a resectable state, select patients with favourable tumour biology for surgery, improve margins, decrease node positivity, and control micrometastases [37][38][39]. A significant survival benefit has been observed with NACT for BR, LA, and early (upfront resectable) PDAC [40][41][42]. For many, the combination of adjuvant and neoadjuvant CT/RT has the greatest impact on OS [43][44][45][46][47], though treatment success can be influenced by many variables, including patient age or the location of disease in the pancreas [48][49][50][51]. Unfortunately, as ~50% of cases are metastatic at presentation, and many additional patients develop local recurrences or metastases during treatment [52][53][54], most patients end up receiving palliative CT. In this setting, one study found that OS was 11.1 months for FFX and 6.8 months for Gem, with median response rates of 31.6% and 9.4%, respectively [55]. Another study found that the response rate of metastatic PDAC to Gem was just 7%, with an OS of 6.7 months, whereas the combination of Gem plus nab-paclitaxel (GnP) gave rise to a better response of 23%, with an OS of 8.5 months [56]. FFX and GnP remain the recommended palliative treatments for PDAC [57].
As most cases of PDAC are highly refractory to systemic treatments, including chemo- and radiotherapies, and their benefit to survival is very low, various targeted agents have been investigated in combination alongside classical cytotoxics [58][59][60]. These are designed around several key areas, including PDAC cell metabolism, deoxyribonucleic acid (DNA) repair, immune response, and the tumour microenvironment (TME). Whilst some have shown promising results in early studies, few have achieved more than a marginal benefit in DFS or OS in larger randomised trials [61][62][63][64]. This lack of efficacy may stem from inter- and intra-tumoural heterogeneity, lack of specific biomarkers to predict effectiveness of target blocking, the use of specific CT regimens, adverse effects necessitating dose reduction, development of resistance, or, most notably, the dense, hypovascularised stroma [9][65][66]. The PDAC stroma contributes to drug resistance by preventing the entry of therapeutic agents into tumour cells, restricting their anti-tumour effects [67][68][69]. Destroying the stroma could alleviate this and improve patient outcomes. However, many initial anti-stromal therapies for PDAC have had toxic effects, lacked efficacy, and added little to DFS or OS [70][71][72]. Some have even been associated with accelerated PDAC progression [73][74]. An alternative solution is the use of PDT, which has not only proven to be feasible and safe for the destruction of PDAC cells [75][76][77] but might also play a role in stromal depletion [78][79][80]. Generally, PDT is well tolerated and does not depend on any specific molecular aberrations, making it applicable to more patients. One possibility is that by destroying the stroma, PDT could enhance the activity of targeted agents as well as traditional cytotoxics. 

2. The PDAC Tumour Microenvironment and Its Regulation

The PDAC tumour microenvironment (TME) describes the confinement of a pancreatic tumour and the extensive constituents that surround and support it. The TME has two compartments: the stroma and the ECM. Whilst the ECM more specifically comprises non-cellular structural proteins, including collagens I, III, IV and V, integrins, proteoglycans, and glycoproteins [81], the stroma contains an extensive mix of fibroblasts, bone marrow-derived stem cells, pancreatic stellate cells (PSCs), immune cells, neurons, and blood and lymphatic vessels, as well as the ECM [82]. The most prominent immune cells are myeloid-derived suppressor cells (MDSCs), macrophages, mast, and effector T-cells [83]. Together, these produce an immunosuppressive effect resulting in the reduction in the anti-tumour activity of the immune system [84].
In PDAC, the desmoplastic reaction describes the initial and continued production of ECM in response to an invasive carcinoma [85]. As the reaction proceeds, the area becomes stiffened and increasingly dense, and eventually, the TME adopts very different mechanical and biophysical traits compared to those of healthy pancreatic tissue [86].
The close link between these TME components and PDAC progression (Figure 2) has led to the development of various stromal depletion strategies, though most have failed. It is theorised that this is because the TME is highly heterogeneous between and within PDAC tumours [87]. By reviewing 143 treatment-naïve resections and pre-treatment biopsies from over 200 cases of advanced PDAC, a 2021 study noted several recurrent histological patterns in the TME and named these ‘subTMEs’ [88]. There were three regions identified: ‘deserted’, characterised by a keloid or myxoid type ECM with thin, spindle-shaped fibroblasts; ‘reactive’, where the ECM comprises very few acellular components, and yet the fibroblasts are enlarged; or there are those with features of both. Comparing the TME and tumour cell samples, there were 5050 differentially expressed genes (DEGs) and 12,704 ribonucleic acid (RNA) DEGs, including known TME markers such as platelet-derived growth factor receptor alpha (PDGFRA). Tissue microarray (TMA) analyses of resections showed that deserted subTMEs had increased collagen content and B-cell marker (cluster of differentiation 20 or CD20) expression, whereas the reactive subTMEs had higher staining for cancer-associated fibroblasts (CAF), macrophages, T-cells, and endothelial cells. Of clinical interest, the co-occurrence of sub-TMEs in 53% of resections was a poor prognostic variable, as was the presence of a ‘deserted subTME’ due to its protective effect against Gem, GnP, and FFX. Though the effect of the TME subtype on the efficacy of anti-stromal agents has not yet been investigated, several other studies have highlighted variations in stromal composition and assigned a prognostic significance [89][90]. Moffitt et al. (2015) [89] used primary and metastatic TMA data to digitally separate the gene expression between PDAC stroma and normal tissue samples. The samples were clustered into three groups: those with ‘activated stroma’, ‘normal stroma’, or ‘absent stromal gene expression’. Kaplan–Meier analyses showed that the ‘activated stroma’ group had worse prognosis, with a median survival time of 15 months and a 1-year survival rate of 60% vs. 24 months and 82% in the ‘normal stroma’ group.
Figure 2. The main PDAC TME components and tumourigenic signalling pathways. The TME is a complex mixture of structural (ECM) and cellular components that play a reciprocal role in the progression of the stroma and the cancer itself. Facilitating many of the interactions between the tumour and stromal components are integrins. Via connecting proteins FN-1/VN-1, collagens interact with the integrins on the PDAC cell surface, which activates FAK and converts actin polymerisation into traction force, driving tumour cell invasion. Collagen also interacts with DDR-1, which binds and activates several signalling proteins, including PYK2, leading to the upregulation of pro-survival genes such as Hes1 and migratory pathways via p130Cas/JNK. The result is the upregulation of N-cad, which promotes the EMT and acquisition of a motile phenotype. Upon Shh pathway activation, PSCs form CAFs, which are the greatest producer of the ECM components, including collagen, PG, and HA. Secreted proteins SPARC, LOX, and TG2 mediate collagen crosslinking, which leads to tissue stiffness, the production of further collagen, and the activation of YAP/TAZ, which promotes cell proliferation. MMPs, which are upregulated by integrin signalling, also modulate the proteolytic activity of the matrices, leading to the release of individual PDAC cells from the TME. Cytokines such as TGF-β and IL-1 released from the PDAC secretome have many functions, including promotion of further collagen production, activation of CAFs, and the adhesion of PDAC cells to capillaries. Activated fibroblasts have several functions: MFs are crucial for the continued deposition of ECM components, whereas ICAFs release various tumour-promoting inflammatory molecules such as IL-6, which enhance the formation of the immunosuppressive environment by regulating immune cell activity. They also support the metabolism of PDAC cells, such as by providing them with labile iron for survival or acting as a cellular reservoir for vitamin A and lipids. BV, blood vessel; RBC, red blood cell; PSC, pancreatic stellate cell; CAF, cancer-associated fibroblast; MDSC, myeloid-derived suppressor cell; TGF-β, transforming growth factor beta; HA, hyaluronan; FN-1, fibronectin 1; VN, vitronectin; DDR-1/2, discoidin receptor ½; PYK2, FAK-related protein tyrosine kinase; FAK, focal adhesion kinase; MMP, matrix metalloproteinase; TG2, tissue transglutimase; LOX, lysyl oxidase; Shh, sonic hedgehog; FGF2, fibroblast growth factor 2; YAP, yes-associated protein; TAZ, transcriptional co-activator with PDZ-binding motif; ICAF, inflammatory cancer-associated fibroblast; MF, myofibroblast; A-PSC, activated pancreatic stellate cell; PG, proteoglycan; SPARC, secreted protein acidic and rich in cysteine; EMT, epithelial to mesenchymal transition; IL-6, interleukin 6; IL-1, interleukin 1; Fe, iron; PDAC, pancreatic ductal adenocarcinoma; JNK, c-Jun N-terminal kinase; N-cad, n-cadherin; TME, tumour microenvironment; ECM, extracellular matrix; SMAD, mothers against decapentaplegic; Ptch1, patched-1 receptor. The figure was created on Biorender.com (accessed on 5 January 2023).
It has since been suggested that pancreatic cancer stem cells (PCSCs) could be responsible for the stromal variation and subsequent effects on disease outcomes in PDAC [91]. As cluster of differentiation-44 (CD44) and epithelial-specific antigen (ESA) are PCSC cell surface markers, one study analysed PDAC surgical resection tissue (n = 93) and found that a ‘loose’ stroma with fewer fibroblasts was highest in CD44+/ESA− (63%) and CD44+/ESA+ (50%) tumours and that a dense, fibroblast-rich stroma was highest in CD44−/ESA− tumours. In a 20-month follow-up study, no local recurrence was observed in patients with dense stroma, with the highest rate of recurrence seen in loose stroma (7% [95%CI: 1–19%] at 1 year and 18% [95%CI: 6–35%] at 3 years) (n = 31), but this was not statistically significant (p = 0.230). Loose stroma was linked to shorter OS (median of 16.1 months [95%CI: 12.4–32.8] vs. 48.5 [95%CI: 16.0–NR]) as compared to dense stroma (p  =  0.025). After adjusting for nodal status, this was not significant (p = 0.061). Despite this, the data suggest that stemness is linked to a loose stroma and worse outcomes in PDAC, suggesting that the stem cell compartment may dictate features of the stroma through differentiation of its components. Taken together, this suggests a need for patient stratification based on stromal heterogeneity, though in the context of PDT it is unclear what effect this would have.

3. PDT Mechanism and Clinical Progress

PDT is a form of photoactive therapy that elicits a cytotoxic effect via the release of reactive oxygen species (ROS) using a light-activated photosensitiser (PS). The treatment is somewhat specific owing to the partially selective accumulation of the drug within the target tissue and the targeting of the light to the tumour and its direct surroundings. The attractiveness of this approach has led to its use for several diseases, including oesophageal, mouth, and lung cancer [92][93][94]. PDT has proved efficacious in destroying advanced PDAC tumours in preclinical and clinical trials, though investigation is ongoing. The mechanism of PDT is well understood. Once the PS molecule is irradiated with a light wavelength corresponding to its absorption spectrum, it undergoes excitation, and the reaction proceeds down one of two routes (Figure 3). The type 2 reaction, where energy is transferred to a ground-state triplet oxygen molecule to form highly reactive singlet oxygen, is most common amongst currently approved PS molecules. This then exerts its effect on the target tissue via the introduction of oxidative stress and the subsequent destruction of various cellular components [95]. The damage directly initiates cytotoxic death via several forms, including apoptosis, autophagy, and necrosis, though other less common modes of death have been noted [96]. PDT also has two indirect effects: the instigation of a ROS-initiated inflammatory response causing an immune reaction and the injury of vascular endothelial cells leading to tumour vessel damage and the obstruction of blood flow. Importantly, the blocking of this flow is dependent on the timing between the drug and light applications (the drug–light interval or DLI). A shorter light application time following drug application favours this process. These responses play a significant role in light-mediated tumour destruction, with many protocols now being modified to enhance them further [97][98][99]. However, for PDT-mediated stromal depletion, there are practical considerations when targeting vascular and immune cell components owing to the diverse roles and heterogeneity of the PDAC stroma.
Figure 3. The mechanism of action PDT. After the photosensitiser (PS) is taken up by the cancer cell, light is delivered to the treatment area and absorbed by the PS, which adopts an excited singlet state (1PS). The PS is transferred to an excited triplet state (3PS) through the process of intersystem crossing and transfers an electron to biological molecules to form free radicals, including the hydroxyl radical (OH), hydroperoxyl radical (HO2), or the superoxide anion radical (O2−) (Type 1 reaction), or transfers energy directly to tissue oxygen, generating unstable singlet oxygen (1O2) (Type 2 reaction). Inside the cell, these highly reactive molecules lead to oxidative stress and DNA damage, rendering the cell susceptible to several forms of death, including apoptosis, necrosis, or autophagy. This figure was created on Biorender.com (accessed on 5 January 2023).
The benefits of PDT include its ability to alter specific cellular targets depending on how the therapy is used. Factors such as the type of PS, light dose, light–dose interval, and drug dose–light dose interval all have an impact on the cytotoxic effect [100][101]. For example, different photosensitisers tend to localise within different organelles; this determines the type of cell death due to the initiation of different signalling pathways [102][103]. The PS can also be modified to increase targeting to the tumour vasculature, rather than the cancer cells [99][104]. Whilst these data have previously only been used to improve the efficacy of PDT and decrease its off-target effects, this control could be leveraged in the context of stromal depletion to achieve a balance between its destruction and maintenance.

Clinical Application of PDT for PDAC

PDT using mTHPC (meta-tetra(hydroxyphenyl)chlorin) first entered clinical trials for PDAC in 2002 [105]. The first study established the efficacy and technical feasibility of percutaneous, computerised tomography (CT)-guided light delivery for PDT in unresectable PDAC. A median survival time of 9.5 months after PDT was recorded. The next trial used a shorter-acting PS, Verteporfin, which enabled better penetration of light to the tissue [75]. A year later, the first phase I trial of the endoscopic ultrasound (EUS)-guided, flexible laser light catheter PDT was performed, and no negative effects were observed [106]. A 2018 trial confirmed these results using Porfimer Sodium (Concordia Laboratories Inc, St Michael, Barbados) [76]. Patients were given Gem/GnP following PDT, and the median OS was 11.5 months. The most recent 2021 study of EUS-guided Verteporfin-mediated PDT had a median OS of 6.8 months [77]. It is difficult to draw conclusions regarding survival advantages from small, nonrandomised studies with few participants and a variable treatment history. In some instances, subsequent oncological treatments were given. Though larger, randomised studies are required to address this, the clinical trials so far have suggested a useful role for PDT as a (neo)adjuvant in PDAC, or even as a single therapy. In addition, all the studies were of patients with LA disease who either did not respond to previous CT or were unsuitable for surgery. It is only within this patient population that PDT has so far been examined, though its use for stromal depletion may be more useful for different stages of PDAC.

4. Role of PDAC Stroma and Implications for PDT

The dense peri-tumoral stroma in PDAC imparts an array of molecular and biophysical effects on the tumour and its constituents (Figure 4). Together, these are responsible for the restriction of the delivery of treatments to the site, which is thought to be one of the reasons for poor survival. Whilst this cancer protective effect could be addressed using PDT-mediated stromal depletion, these challenges are extended to the successful clinical implementation of PDT for two reasons. Firstly, the desmoplastic reaction creates a dense environment with high compressive stress that causes blood and lymph vessels to be occluded; analysis of MMTV-M3C breast tumours showed that the fraction of perfused vessels decreased with tumour size and an associated higher level of stress [107]. This is contributed to the hygroscopic nature of hyaluronic acid (HA), which causes the localised trapping of water [108]. One study investigated orthotopic MiaPaCa2 PDAC tumours and found that the swelling stress was 16.01 ± 1.66 mmHg (2.13 ± 0.22 kPa), whereas in healthy tissues this was much lower, usually around zero [109]. This was linearly proportional to the ratio of the HA/collagen area fraction (n = 5) and could be decreased experimentally by hyaluronidase, an enzyme that breaks down HA. Analysis of perfused blood vessels as a function of tumour swelling showed that there was an exponential decay relationship in vivo, suggesting their physical occlusion. Once the vessels are occluded, IFP, which is zero in normal tissues, rises and equilibrates with microvascular pressure as the extracellular fluid cannot drain [110]. Analysis of PDAC tumour IFP levels in genetically engineered KPC mice, which act as a clinically relevant model of PDAC, have been reported as being as high as 76 ± 4.2 mmHg vs. −0.73 ± 0.6 mmHg in the normal mouse pancreas [111]. Whilst abnormal angiogenesis usually contributes to leaky vasculature in many solid tumour types, where drugs are able to exit the bloodstream more easily via the enhanced permeability and retention (EPR) effect, the occlusion and eventual collapse of blood vessels in PDAC as a result of the high pressure imposed by the stroma prevents this [108]. As the movement of macromolecules into the tumour is prevented, drug delivery is restricted. A 2022 study found that serum concentrations of ‘free’ doxorubicin (Dox) in subcutaneous mouse PDAC tumours were just 0.8 µg/mL 15 min after administration, and the drug was cleared entirely by 4 h [112]. The same challenges are faced with the entry of PS agents in PDAC [113]. Secondly, the lack of oxygen transport makes the TME hypoxic, which restricts the efficacy of PDT by limiting light penetration as well as the actual cytotoxic effect (as this is dependent on the presence of molecular oxygen). The hypoxia also feeds into the desmoplastic reaction, which perpetuates the effect further [114]. Careful depletion of the PDAC stroma by PDT might allow these obstacles to be overcome.
Figure 4. The overall physical and biophysical effects of the PDAC stroma on the tumour and its TME. The unique stroma in PDAC has a broad range of implications that prevent the delivery of therapeutic agents, mainly via their effects on blood vessels. This includes high levels of IFP, solid stress, and tissue stiffness. Adding to this effect is the unusual morphology of the vessels, owing to abnormal angiogenesis characteristic of the disease. The result of these features creates a harsh environment where PDAC cells are subject to nutrient deprivation, severe hypoxia, and immune suppression. This contributes to tumourigenesis and is further enhanced by the production of cytokines which interfere with PDAC cell–cell junctions and their mechanotransducive properties. As a result, PDAC cells gain a more migratory and invasive phenotype. IFP, interstitial fluid pressure. This figure was created on Biorender.com (accessed on 5 January 2023).

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  2. Ferlay, J.; Partensky, C.; Bray, F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 2016, 55, 1158–1160.
  3. Adamska, A.; Domenichini, A.; Falasca, M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int. J. Mol. Sci. 2017, 18, 1338.
  4. Schawkat, K.; Manning, M.A.; Glickman, J.N.; Mortele, K.J. Pancreatic Ductal Adenocarcinoma and Its Variants: Pearls and Perils. Radiographics 2020, 40, 1219–1239.
  5. Ansari, D.; Carvajo, M.; Bauden, M.; Andersson, R. Pancreatic cancer stroma: Controversies and current insights. Scand. J. Gastroenterol. 2017, 52, 641–646.
  6. Liot, S.; Balas, J.; Aubert, A.; Prigent, L.; Mercier-Gouy, P.; Verrier, B.; Bertolino, P.; Hennino, A.; Valcourt, U.; Lambert, E. Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins. Front. Immunol. 2021, 12, 612271.
  7. Thomas, D.; Radhakrishnan, P. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol. Cancer 2019, 18, 14.
  8. Anderson, E.M.; Thomassian, S.; Gong, J.; Hendifar, A.; Osipov, A. Advances in Pancreatic Ductal Adenocarcinoma Treatment. Cancers 2021, 13, 5510.
  9. Du, J.; Gu, J.; Li, J. Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels. Biosci. Rep. 2020, 40, BSR20200401.
  10. Braun, R.; Klinkhammer-Schalke, M.; Zeissig, S.R.; van Tol, K.K.; Bolm, L.; Honselmann, K.C.; Petrova, E.; Lapshyn, H.; Deichmann, S.; Abdalla, T.S.A.; et al. Clinical Outcome and Prognostic Factors of Pancreatic Adenosquamous Carcinoma Compared to Ductal Adenocarcinoma—Results from the German Cancer Registry Group. Cancers 2022, 14, 3946.
  11. Evans, D.B.; Ben George, B.; Tsai, S. Non-metastatic Pancreatic Cancer: Resectable, Borderline Resectable, and Locally Advanced-Definitions of Increasing Importance for the Optimal Delivery of Multimodality Therapy. Ann. Surg. Oncol. 2015, 22, 3409–3413.
  12. Varadhachary, G.R.; Tamm, E.P.; Crane, C.; Evans, D.B.; Wolff, R.A. Borderline resectable pancreatic cancer. Curr. Treat. Opt. Gastroenterol. 2005, 8, 377–384.
  13. Isaji, S.; Mizuno, S.; Windsor, J.A.; Bassi, C.; Castillo, C.F.-D.; Hackert, T.; Hayasaki, A.; Katz, M.H.; Kim, S.-W.; Kishiwada, M.; et al. International consensus on definition and criteria of borderline resectable pancreatic ductal adenocarcinoma 2017. Pancreatology 2018, 18, 2–11.
  14. Nießen, A.; Hackert, T. State-of-the-art surgery for pancreatic cancer. Langenbeck’s Arch. Surg. 2021, 407, 443–450.
  15. Groot, V.P.; Rezaee, N.; Wu, W.; Cameron, J.L.; Fishman, E.K.; Hruban, R.H.; Weiss, M.J.; Zheng, L.; Wolfgang, C.L.; He, J. Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma. Ann. Surg. 2018, 267, 936–945.
  16. Groot, V.P.; Gemenetzis, G.; Blair, A.B.; Rivero-Soto, R.J.; Yu, J.; Javed, A.A.; Burkhart, R.A.; Rinkes, I.H.M.B.; Molenaar, I.Q.; Cameron, J.L.M.; et al. Defining and Predicting Early Recurrence in 957 Patients with Resected Pancreatic Ductal Adenocarcinoma. Ann. Surg. 2019, 269, 1154–1162.
  17. Parikh, A.A.; Maiga, A.; Bentrem, D.; Squires, M.H., III; Kooby, D.A.; Maithel, S.K.; Weber, S.M.; Cho, C.S.; Katz, M.; Martin, R.C.; et al. Adjuvant Therapy in Pancreas Cancer: Does It Influence Patterns of Recurrence? J. Am. Coll. Surg. 2016, 222, 448–456.
  18. Shinde, R.S.; Bhandare, M.; Chaudhari, V.; Shrikhande, S.V. Cutting-edge strategies for borderline resectable pancreatic cancer. Ann. Gastroenterol. Surg. 2019, 3, 368–372.
  19. Oettle, H.; Neuhaus, P.; Hochhaus, A.; Hartmann, J.T.; Gellert, K.; Ridwelski, K.; Niedergethmann, M.; Zülke, C.; Fahlke, J.; Arning, M.B.; et al. Adjuvant Chemotherapy with Gemcitabine and Long-term Outcomes among Patients with Resected Pancreatic Cancer. JAMA 2013, 310, 1473–1481.
  20. Oettle, H.; Post, S.; Neuhaus, P.; Gellert, K.; Langrehr, J.; Ridwelski, K.; Schramm, H.; Fahlke, J.; Zuelke, C.; Burkart, C.; et al. Adjuvant Chemotherapy with Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer. JAMA 2007, 297, 267–277.
  21. Conroy, T.; Hammel, P.; Hebbar, M.; Ben Abdelghani, M.; Wei, A.C.; Raoul, J.-L.; Choné, L.; Francois, E.; Artru, P.; Biagi, J.J.; et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N. Engl. J. Med. 2018, 379, 2395–2406.
  22. Wu, W.; He, J.; Cameron, J.L.; Makary, M.; Soares, K.; Ahuja, N.; Rezaee, N.; Herman, J.; Zheng, L.; Laheru, D.; et al. The Impact of Postoperative Complications on the Administration of Adjuvant Therapy Following Pancreaticoduode-nectomy for Adenocarcinoma. Ann. Surg. Oncol. 2014, 21, 2873–2881.
  23. Merkow, R.P.; Bilimoria, K.Y.; Tomlinson, J.S.; Paruch, J.L.; Fleming, J.B.; Talamonti, M.S.; Ko, C.Y.; Bentrem, D.J. Postoperative Complications Reduce Adjuvant Chemotherapy Use in Resectable Pancreatic Cancer. Ann. Surg. 2014, 260, 372–377.
  24. Åkerberg, D.; Björnsson, B.; Ansari, D. Factors influencing receipt of adjuvant chemotherapy after surgery for pancreatic cancer: A two-center retrospective cohort study. Scand. J. Gastroenterol. 2016, 52, 56–60.
  25. Labori, K.J.; Katz, M.H.; Tzeng, C.W.; Bjørnbeth, B.A.; Cvancarova, M.; Edwin, B.; Kure, E.H.; Eide, T.J.; Dueland, S.; Buanes, T.; et al. Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma—A population-based cohort study. Acta Oncol. 2015, 55, 265–277.
  26. Tzeng, C.-W.D.; Cao, H.S.T.; Lee, J.E.; Pisters, P.W.; Varadhachary, G.R.; Wolff, R.A.; Abbruzzese, J.L.; Crane, C.H.; Evans, D.B.; Wang, H.; et al. Treatment Sequencing for Resectable Pancreatic Cancer: Influence of Early Metastases and Surgical Complications on Multimodality Therapy Completion and Survival. J. Gastrointest. Surg. 2013, 18, 16–25.
  27. Muhammadzai, J.; Haider, K.; Moser, M.; Chalchal, H.; Shaw, J.; Gardiner, D.; Dueck, D.-A.; Ahmed, O.; Brunet, B.; Iqbal, M.; et al. Early discontinuation of adjuvant chemotherapy in patients with early-stage pancreatic cancer correlates with inferior survival: A multicenter population-based cohort study. PLoS ONE 2022, 17, e0263250.
  28. Schwarz, L.; Bruno, M.; Parker, N.H.; Prakash, L.; Mise, Y.; Lee, J.E.; Vauthey, J.-N.; Aloia, T.A.; Conrad, C.; Fleming, J.B.; et al. Active Surveillance for Adverse Events within 90 Days: The Standard for Reporting Surgical Outcomes after Pancreatectomy. Ann. Surg. Oncol. 2015, 22, 3522–3529.
  29. Polani, F.; Grierson, P.M.; Lim, K.-H. Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects. World J. Gastroenterol. 2021, 27, 2105–2121.
  30. Picozzi, V.J.; Stephen, O.-H.; Edwards, A.; Mandelson, M.T.; Dorer, R.; Rocha, F.G.; Alseidi, A.; Biehl, T.; Traverso, W.L.; Helton, W.S.; et al. Five-Year Actual Overall Survival in Resected Pancreatic Cancer: A Contemporary Single-Institution Experience from a Multidisciplinary Perspective. Ann. Surg. Oncol. 2017, 24, 1722–1730.
  31. Neoptolemos, J.P.; Stocken, D.D.; Bassi, C.; Ghaneh, P.; Cunningham, D.; Goldstein, D.; Padbury, R.; Moore, M.J.; Gallinger, S.; Mariette, C.; et al. Adjuvant Chemotherapy with Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection. JAMA 2010, 304, 1073–1081.
  32. Sinn, M.; Bahra, M.; Liersch, T.; Gellert, K.; Messmann, H.; Bechstein, W.; Waldschmidt, D.; Jacobasch, L.; Wilhelm, M.; Rau, B.M.; et al. CONKO-005: Adjuvant Chemotherapy with Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients after R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial. J. Clin. Oncol. 2017, 35, 3330–3337.
  33. Chikhladze, S.; Lederer, A.-K.; Kousoulas, L.; Reinmuth, M.; Sick, O.; Fichtner-Feigl, S.; Wittel, U.A. Adjuvant chemotherapy after surgery for pancreatic ductal adenocarcinoma: Retrospective real-life data. World J. Surg. Oncol. 2019, 17, 185.
  34. Strobel, O.; Lorenz, P.; Hinz, U.M.; Gaida, M.; König, A.-K.; Hank, T.; Niesen, W.; Kaiser, J.; Al-Saeedi, M.; Bergmann, F.; et al. Actual Five-year Survival after Upfront Resection for Pancreatic Ductal Adenocarcinoma. Ann. Surg. 2020, 275, 962–971.
  35. Moaven, O.; Clark, C.J.; Russell, G.B.M.; Votanopoulos, K.I.; Howerton, R.; Levine, E.A.; Shen, P. Optimal Adjuvant Treatment Approach after Upfront Resection of Pancreatic Cancer. Ann. Surg. 2020, 274, 1058–1066.
  36. Lim, K.H.; Chung, E.; Khan, A.; Cao, D.; Linehan, D.; Ben-Josef, E.; Wang-Gillam, A. Neoadjuvant Therapy of Pancreatic Cancer: The Emerging Paradigm? Oncologist 2012, 17, 192–200.
  37. Strobel, O.; Neoptolemos, J.; Jäger, D.; Büchler, M.W. Optimizing the outcomes of pancreatic cancer surgery. Nat. Rev. Clin. Oncol. 2019, 16, 11–26.
  38. Reni, M.; Balzano, G.; Zanon, S.; Zerbi, A.; Rimassa, L.; Castoldi, R.; Pinelli, D.; Mosconi, S.; Doglioni, C.; Chiaravalli, M.; et al. Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): A randomised, open-label, phase 2–3 trial. Lancet Gastroenterol. Hepatol. 2018, 3, 413–423.
  39. Heinrich, S.; Schäfer, M.; Weber, A.; Hany, T.F.; Bhure, U.; Pestalozzi, B.C.; Clavien, P.-A.M. Neoadjuvant Chemotherapy Generates a Significant Tumor Response in Resectable Pancreatic Cancer without Increasing Morbidity. Ann. Surg. 2008, 248, 1014–1022.
  40. Shridhar, R.; Takahashi, C.; Huston, J.; Meredith, K.L. Neoadjuvant therapy and pancreatic cancer: A national cancer database analysis. J. Gastrointest. Oncol. 2019, 10, 663–673.
  41. Deng, A.; Wang, C.; Cohen, S.J.; Winter, J.M.; Posey, J.; Yeo, C.; Mallick, A.B. Multi-agent neoadjuvant chemotherapy improves survival in early-stage pancreatic cancer: A National Cancer Database analysis. Eur. J. Cancer 2021, 147, 17–28.
  42. Deig, C.R.; Sutton, T.L.; Beneville, B.; Trone, K.; Stratton, A.; Gunesch, A.N.; Liu, A.I.; Alrohaibani, A.; Mohebnasab, M.; Bassale, S.; et al. Neoadjuvant Therapy Is Associated with Improved Chemotherapy Delivery and Overall Survival Compared to Upfront Resection in Pancreatic Cancer without Increasing Perioperative Complications. Cancers 2022, 14, 609.
  43. Kamarajah, S.K.; White, S.A.; Naffouje, S.A.; Salti, G.I.; Dahdaleh, F. Adjuvant Chemotherapy Associated with Survival Benefit Following Neoadjuvant Chemotherapy and Pancreatectomy for Pancreatic Ductal Adenocarcinoma: A Population-Based Cohort Study. Ann. Surg. Oncol. 2021, 28, 6790–6802.
  44. Brunner, T.B.; Scott-Brown, M. The role of radiotherapy in multimodal treatment of pancreatic carcinoma. Radiat. Oncol. 2010, 5, 64.
  45. Mukherjee, S.; Hurt, C.N.; Bridgewater, J.; Falk, S.; Cummins, S.; Wasan, H.; Crosby, T.; Jephcott, C.; Roy, R.; Radhakrishna, G.; et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): A multicentre, randomised, phase 2 trial. Lancet Oncol. 2013, 14, 317–326.
  46. Wang, D.; Liu, C.; Zhou, Y.; Yan, T.; Li, C.; Yang, Q.; Xu, Y.; Zhao, L.; Pei, Q.; Tan, F.; et al. Effect of neoadjuvant radiotherapy on survival of non-metastatic pancreatic ductal adenocarcinoma: A SEER database analysis. Radiat. Oncol. 2020, 15, 107.
  47. Wang, D.; Ge, H.; Tian, M.; Li, C.; Zhao, L.; Pei, Q.; Tan, F.; Li, Y.; Ling, C.; Güngör, C. The Survival Effect of Radiotherapy on Stage IIB/III Pancreatic Cancer Undergone Surgery in Different Age and Tumor Site Groups: A Propensity Scores Matching Analysis Based on SEER Database. Front. Oncol. 2022, 12, 799930.
  48. Saadat, L.V.; Chou, J.F.; Gonen, M.; Soares, K.C.; Kingham, T.P.; Varghese, A.M.; Jarnagin, W.R.; D’angelica, M.I.; Drebin, J.A.; O’reilly, E.M.; et al. Treatment patterns and survival in patients with early-onset pancreatic cancer. Cancer 2021, 127, 3566–3578.
  49. Ansari, D.; Althini, C.; Ohlsson, H.; Andersson, R. Early-onset pancreatic cancer: A population-based study using the SEER registry. Langenbeck’s Arch. Surg. 2019, 404, 565–571.
  50. Winer, L.K.; Dhar, V.K.; Wima, K.; Morris, M.C.; Lee, T.C.; Shah, S.A.; Ahmad, S.A.; Patel, S.H. The Impact of Tumor Location on Resection and Survival for Pancreatic Ductal Adenocarcinoma. J. Surg. Res. 2019, 239, 60–66.
  51. Takeda, T.; Sasaki, T.; Inoue, Y.; Mie, T.; Furukawa, T.; Kanata, R.; Kasuga, A.; Matsuyama, M.; Ozaka, M.; Takahashi, Y.; et al. Comprehensive comparison of clinicopathological characteristics, treatment, and prognosis of borderline resectable pancreatic cancer according to tumor location. Pancreatology 2020, 20, 1123–1130.
  52. Peixoto, R.D.; Speers, C.; McGahan, C.E.; Renouf, D.J.; Schaeffer, D.F.; Kennecke, H.F. Prognostic factors and sites of metastasis in unresectable locally advanced pancreatic cancer. Cancer Med. 2015, 4, 1171–1177.
  53. Truty, M.J.; Kendrick, M.L.; Nagorney, D.M.; Smoot, R.L.; Cleary, S.P.; Graham, R.P.; Goenka, A.H.; Hallemeier, C.L.; Haddock, M.G.; Harmsen, W.S.; et al. Factors Predicting Response, Perioperative Outcomes, and Survival Following Total Neoadjuvant Therapy for Borderline/Locally Advanced Pancreatic Cancer. Ann. Surg. 2019, 273, 341–349.
  54. Miquel, M.; Zhang, S.; Pilarsky, C. Pre-clinical Models of Metastasis in Pancreatic Cancer. Front. Cell Dev. Biol. 2021, 9, 748631.
  55. Conroy, T.; Desseigne, F.; Ychou, M.; Bouché, O.; Guimbaud, R.; Bécouarn, Y.; Adenis, A.; Raoul, J.-L.; Gourgou-Bourgade, S.; De La Fouchardière, C.; et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N. Engl. J. Med. 2011, 364, 1817–1825.
  56. Von Hoff, D.D.; Ervin, T.; Arena, F.P.; Chiorean, E.G.; Infante, J.; Moore, M.; Seay, T.; Tjulandin, S.A.; Ma, W.W.; Saleh, M.N.; et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. N. Engl. J. Med. 2013, 369, 1691–1703.
  57. Sohal, D.P.S.; Kennedy, E.B.; Khorana, A.; Copur, M.S.; Crane, C.H.; Garrido-Laguna, I.; Krishnamurthi, S.; Moravek, C.; O’Reilly, E.M.; Philip, P.A.; et al. Metastatic Pancreatic Cancer: ASCO Clinical Practice Guideline Update. J. Clin. Oncol. 2018, 36, 2545–2556.
  58. Thomas, A.G.; Awasthi, N. Targeted therapy for pancreatic cancer: Lessons learned and future opportunities. Dig. Med. Res. 2021, 4, 32.
  59. Hosein, A.N.; Dougan, S.K.; Aguirre, A.J.; Maitra, A. Translational advances in pancreatic ductal adenocarcinoma therapy. Nat. Cancer 2022, 3, 272–286.
  60. Grinshpun, A.; Zarbiv, Y.; Roszik, J.; Subbiah, V.; Hubert, A. Beyond KRAS: Practical Molecular Targets in Pancreatic Adenocarcinoma. Case Rep. Oncol. 2019, 12, 7–13.
  61. Tempero, M.; Oh, D.-Y.; Tabernero, J.; Reni, M.; Van Cutsem, E.; Hendifar, A.; Waldschmidt, D.-T.; Starling, N.; Bachet, J.-B.; Chang, H.-M.; et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: Phase III RESOLVE study. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2021, 32, 600–608.
  62. Hecht, J.R.; Lonardi, S.; Bendell, J.; Sim, H.-W.; Macarulla, T.; Lopez, C.D.; Van Cutsem, E.; Martin, A.J.M.; Park, J.O.; Greil, R.; et al. Randomized Phase III Study of FOLFOX Alone or with Pegilodecakin as Second-Line Therapy in Patients with Metastatic Pancreatic Cancer That Progressed after Gemcitabine (SEQUOIA). J. Clin. Oncol. 2021, 39, 1108–1118.
  63. Shin, S.; Park, C.M.; Kwon, H.; Lee, K.-H. Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: Real-world analysis of Korean national database. BMC Cancer 2016, 16, 443.
  64. Hammel, P.; Huguet, F.; van Laethem, J.L.; Goldstein, D.; Glimelius, B.; Artru, P.; Borbath, I.; Bouché, O.; Shannon, J.; André, T.; et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients with Locally Advanced Pancreatic Cancer Controlled after 4 Months of Gemcitabine with or without Erlotinib: The LAP07 Randomized Clinical Trial. JAMA 2016, 315, 1844–1853.
  65. Di Marco, M.; Grassi, E.; Durante, S.; Vecchiarelli, S.; Palloni, A.; Macchini, M.; Casadei, R.; Ricci, C.; Panzacchi, R.; Santini, D.; et al. State of the art biological therapies in pancreatic cancer. World J. Gastrointest. Oncol. 2016, 8, 55–66.
  66. Safran, H.; Miner, T.; Bahary, N.; Whiting, S.; Lopez, C.D.; Sun, W.; Charpentier, K.; Shipley, J.; Anderson, E.; McNulty, B.; et al. Lapatinib and Gemcitabine for Metastatic Pancreatic Cancer. Am. J. Clin. Oncol. 2011, 34, 50–52.
  67. Jacobetz, M.A.; Chan, D.S.; Neesse, A.; Bapiro, T.E.; Cook, N.; Frese, K.K.; Feig, C.; Nakagawa, T.; Caldwell, M.E.; Zecchini, H.I.; et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013, 62, 112–120.
  68. Ireland, L.; Santos, A.; Ahmed, M.S.; Rainer, C.; Nielsen, S.R.; Quaranta, V.; Weyer-Czernilofsky, U.; Engle, D.D.; Perez-Mancera, P.A.; Coupland, S.E.; et al. Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors. Cancer Res. 2016, 76, 6851–6863.
  69. Hu, C.; Xia, R.; Zhang, X.; Li, T.; Ye, Y.; Li, G.; He, R.; Li, Z.; Lin, Q.; Zheng, S.; et al. circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis. Mol. Cancer 2022, 21, 24.
  70. Jimeno, A.; Weiss, G.J.; Miller, W.H.; Gettinger, S.; Eigl, B.J.; Chang, A.L.S.; Dunbar, J.; Devens, S.; Faia, K.; Skliris, G.; et al. Phase I Study of the Hedgehog Pathway Inhibitor IPI-926 in Adult Patients with Solid Tumors. Clin. Cancer Res. 2013, 19, 2766–2774.
  71. Ko, A.H.; LoConte, N.; Tempero, M.A.; Walker, E.J.; Kelley, R.K.; Lewis, S.; Chang, W.-C.; Kantoff, E.; Vannier, M.W.; Catenacci, D.V.; et al. A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma. Pancreas 2016, 45, 370–375.
  72. Van Cutsem, E.; Tempero, M.A.; Sigal, D.; Oh, D.-Y.; Fazio, N.; Macarulla, T.; Hitre, E.; Hammel, P.; Hendifar, A.E.; Bates, S.E.; et al. Randomized Phase III Trial of Pegvorhyaluronidase Alfa with Nab-Paclitaxel Plus Gemcitabine for Patients with Hyaluronan-High Metastatic Pancreatic Adenocarcinoma. J. Clin. Oncol. 2020, 38, 3185–3194.
  73. Jiang, B.; Zhou, L.; Lu, J.; Wang, Y.; Liu, C.; You, L.; Guo, J. Stroma-Targeting Therapy in Pancreatic Cancer: One Coin with Two Sides? Front. Oncol. 2020, 10, 576399.
  74. Lee, J.J.; Perera, R.M.; Wang, H.; Wu, D.-C.; Liu, X.S.; Han, S.; Fitamant, J.; Jones, P.D.; Ghanta, K.S.; Kawano, S.; et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl. Acad. Sci. USA 2014, 111, E3091–E3100.
  75. Huggett, M.T.; Jermyn, M.; Gillams, A.; Illing, R.; Mosse, S.; Novelli, M.; Kent, E.; Bown, S.G.; Hasan, T.; Pogue, B.W.; et al. Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer. Br. J. Cancer 2014, 110, 1698–1704.
  76. DeWitt, J.M.; Sandrasegaran, K.; O’Neil, B.; House, M.G.; Zyromski, N.J.; Sehdev, A.; Perkins, S.M.; Flynn, J.; McCranor, L.; Shahda, S. Phase 1 study of EUS-guided photodynamic therapy for locally advanced pancreatic cancer. Gastrointest. Endosc. 2019, 89, 390–398.
  77. Hanada, Y.; Pereira, S.P.; Pogue, B.; Maytin, E.V.; Hasan, T.; Linn, B.; Mangels-Dick, T.; Wang, K.K. EUS-guided verteporfin photodynamic therapy for pancreatic cancer. Gastrointest. Endosc. 2021, 94, 179–186.
  78. Karimnia, V.; Rizvi, I.; Slack, F.J.; Celli, J.P. Photodestruction of Stromal Fibroblasts Enhances Tumor Response to PDT in 3D Pancreatic Cancer Coculture Models. Photochem. Photobiol. 2020, 97, 416–426.
  79. Celli, J.P. Stromal Interactions as Regulators of Tumor Growth and Therapeutic Response: A Potential Target for Photodynamic Therapy? Isr. J. Chem. 2012, 52, 757–766.
  80. Jafari, R.; Cramer, G.M.; Celli, J.P. Modulation of Extracellular Matrix Rigidity Via Riboflavin-mediated Photocrosslinking Regulates Invasive Motility and Treatment Response in a 3D Pancreatic Tumor Model. Photochem. Photobiol. 2020, 96, 365–372.
  81. Maneshi, P.; Mason, J.; Dongre, M.; Öhlund, D. Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits. Front. Cell Dev. Biol. 2021, 9, 787485.
  82. Korc, M. Pancreatic cancer–associated stroma production. Am. J. Surg. 2007, 194, S84–S86.
  83. Muller, M.; Haghnejad, V.; Schaefer, M.; Gauchotte, G.; Caron, B.; Peyrin-Biroulet, L.; Bronowicki, J.-P.; Neuzillet, C.; Lopez, A. The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges. Cancers 2022, 14, 995.
  84. Carstens, J.L.; de Sampaio, P.C.; Yang, D.; Barua, S.; Wang, H.; Rao, A.; Allison, J.P.; LeBleu, V.S.; Kalluri, R. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat. Commun. 2017, 8, 15095.
  85. Nielsen, M.F.B.; Mortensen, M.B.; Detlefsen, S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J. Gastroenterol. 2016, 22, 2678–2700.
  86. Kpeglo, D.; Hughes, M.D.; Dougan, L.; Haddrick, M.; Knowles, M.A.; Evans, S.D.; Peyman, S.A. Modeling the mechanical stiffness of pancreatic ductal adenocarcinoma. Matrix Biol. Plus 2022, 14, 100109.
  87. Ogawa, Y.; Masugi, Y.; Abe, T.; Yamazaki, K.; Ueno, A.; Fujii-Nishimura, Y.; Hori, S.; Yagi, H.; Abe, Y.; Kitago, M.; et al. Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen. Clin. Cancer Res. 2021, 27, 107–119.
  88. Grünwald, B.T.; Devisme, A.; Andrieux, G.; Vyas, F.; Aliar, K.; McCloskey, C.W.; Macklin, A.; Jang, G.H.; Denroche, R.; Romero, J.M.; et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell 2021, 184, 5577–5592.e18.
  89. Moffitt, R.A.; Marayati, R.; Flate, E.L.; Volmar, K.E.; Loeza, S.G.H.; Hoadley, K.A.; Rashid, N.U.; Williams, L.A.; Eaton, S.C.; Chung, A.H.; et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 2015, 47, 1168–1178.
  90. Bailey, P.; Chang, D.K.; Nones, K.; Johns, A.L.; Patch, A.-M.; Gingras, M.-C.; Miller, D.K.; Christ, A.N.; Bruxner, T.J.C.; Quinn, M.C.; et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016, 531, 47–52.
  91. Askan, G.; Sahin, I.H.; Chou, J.F.; Yavas, A.; Capanu, M.; Iacobuzio-Donahue, C.A.; Basturk, O.; O’reilly, E.M. Pancreatic cancer stem cells may define tumor stroma characteristics and recurrence patterns in pancreatic ductal adenocarcinoma. BMC Cancer 2021, 21, 385.
  92. Wu, H.; Minamide, T.; Yano, T. Role of photodynamic therapy in the treatment of esophageal cancer. Dig. Endosc. 2019, 31, 508–516.
  93. Saini, R.; Lee, N.V.; Liu, K.Y.; Poh, C.F. Prospects in the Application of Photodynamic Therapy in Oral Cancer and Premalignant Lesions. Cancers 2016, 8, 83.
  94. Crous, A.; Abrahamse, H. Photodynamic therapy of lung cancer, where are we? Front. Pharmacol. 2022, 13, 932098.
  95. Robertson, C.A.; Evans, D.H.; Abrahamse, H. Photodynamic therapy (PDT): A short review on cellular mechanisms and cancer research applications for PDT. J. Photochem. Photobiol. B 2009, 96, 1–8.
  96. Castano, A.P.; Demidova, T.N.; Hamblin, M.R. Mechanisms in PDT: Part three—Photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. Photodiagnosis Photodyn. Ther. 2005, 2, 91–106.
  97. Castano, A.P.; Mroz, P.; Hamblin, M.R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 2006, 6, 535–545.
  98. Mroz, P.; Szokalska, A.; Wu, M.X.; Hamblin, M.R. Photodynamic Therapy of Tumors Can Lead to Development of Systemic Antigen-Specific Immune Response. PLoS ONE 2010, 5, e15194.
  99. Mashayekhi, V.; Op’t Hoog, C.; Oliveira, S. Vascular targeted photodynamic therapy: A review of the efforts towards molecular targeting of tumor vasculature. J. Porphyr. Phthalocyanines 2019, 23, 1229–1240.
  100. Abrahamse, H.; Hamblin Michael, R. New photosensitizers for photodynamic therapy. Biochem. J. 2016, 473, 347–364.
  101. Liu, K.-H.; Wang, C.-P.; Chang, M.-F.; Chung, Y.-W.; Lou, P.-J.; Lin, J.-H. Molecular characterization of photosensitizer-mediated photodynamic therapy by gene expression profiling. Hum. Exp. Toxicol. 2013, 33, 629–637.
  102. Kessel, D. Correlation between subcellular localization and photodynamic efficacy. J. Porphyr. Phthalocyanines 2004, 8, 1009–1014.
  103. Uchoa, A.F.; Oliveira, C.S.; Baptista, M.S. Relationship between structure and photoactivity of porphyrins derived from pro-toporphyrin IX. J. Porphyr. Phthalocyanines 2010, 14, 832–845.
  104. Zhen, Z.; Tang, W.; Chuang, Y.-J.; Todd, T.; Zhang, W.; Lin, X.; Niu, G.; Liu, G.; Wang, L.; Pan, Z.; et al. Tumor Vasculature Targeted Photodynamic Therapy for Enhanced Delivery of Nanoparticles. ACS Nano 2014, 8, 6004–6013.
  105. Bown, S.G.; Rogowska, A.Z.; Whitelaw, D.E.; Lees, W.-R.; Lovat, L.B.; Ripley, P.; Jones, L.; Wyld, P.; Gillams, A.; Hatfield, A.W.R. Photodynamic therapy for cancer of the pancreas. Gut 2002, 50, 549–557.
  106. Choi, J.-H.; Oh, D.; Lee, J.H.; Park, J.-H.; Kim, K.-P.; Lee, S.S.; Lee, Y.-J.; Lim, Y.-S.; Song, T.J.; Lee, S.S.; et al. Initial human experience of endoscopic ultrasound-guided photodynamic therapy with a novel photosensitizer and a flexible laser-light catheter. Endoscopy 2015, 47, 1035–1038.
  107. Nia, H.T.; Liu, H.; Seano, G.; Datta, M.; Jones, D.; Rahbari, N.; Incio, J.; Chauhan, V.P.; Jung, K.; Martin, J.D.; et al. Solid stress and elastic energy as measures of tumour mechanopathology. Nat. Biomed. Eng. 2016, 1, 1.
  108. Gündel, B.; Liu, X.; Löhr, M.; Heuchel, R. Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models. Front. Cell Dev. Biol. 2021, 9, 741162.
  109. Voutouri, C.; Polydorou, C.; Papageorgis, P.; Gkretsi, V.; Stylianopoulos, T. Hyaluronan-Derived Swelling of Solid Tumors, the Contribution of Collagen and Cancer Cells, and Implications for Cancer Therapy. Neoplasia 2016, 18, 732–741.
  110. Boucher, Y.; Jain, R.K. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: Implications for vascular collapse. Cancer Res. 1992, 52, 5110–5114.
  111. DuFort, C.C.; DelGiorno, K.E.; Carlson, M.A.; Osgood, R.J.; Zhao, C.; Huang, Z.; Thompson, C.B.; Connor, R.J.; Thanos, C.D.; Brockenbrough, J.S.; et al. Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase. Biophys. J. 2016, 110, 2106–2119.
  112. Zhao, T.; Zhang, R.; He, Q.; Zhou, H.; Song, X.; Gong, T.; Zhang, Z. Partial ligand shielding nanoparticles improve pancreatic ductal adenocarcinoma treatment via a multifunctional paradigm for tumor stroma reprogramming. Acta Biomater. 2022, 145, 122–134.
  113. Yang, H.; Liu, R.; Xu, Y.; Qian, L.; Dai, Z. Photosensitizer Nanoparticles Boost Photodynamic Therapy for Pancreatic Cancer Treatment. Nano-Micro Lett. 2021, 13, 35.
  114. Shah, V.; Sheppard, B.; Sears, R.; Alani, A.W. Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer. Cancer Lett. 2020, 492, 63–70.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Nicole M. Lintern
,
Andrew M. Smith
,
David G. Jayne
,
Yazan S. Khaled
View Times: 231
Revisions: 2 times (View History)
Update Date: 01 Sep 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback