Cancers

Research

17 pages, 2320 KiB

Open AccessArticle

Ultrasound as a New Method for the Release and Identification of Novel microRNAs and Proteins as Candidate Biomarkers in Pancreatic Cancer

by Veronica Zelli, Alessandra Corrente, Chiara Compagnoni, Francesco Colaianni, Martina Sara Miscione, Monica Di Padova, Daria Capece, Gaetano Barbato, Edoardo Alesse, Francesca Zazzeroni and Alessandra Tessitore

Cancers 2025, 17(12), 1979; https://doi.org/10.3390/cancers17121979 - 13 Jun 2025

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Abstract

Background/Objectives: Pancreatic cancer (PC) is among the most aggressive malignancies, often diagnosed at late stages. MicroRNAs (miRNAs) and proteins released from the tumor microenvironment into body fluids represent promising non-invasive biomarkers for early cancer detection. In this study, we took advantage of an [...] Read more.

Background/Objectives: Pancreatic cancer (PC) is among the most aggressive malignancies, often diagnosed at late stages. MicroRNAs (miRNAs) and proteins released from the tumor microenvironment into body fluids represent promising non-invasive biomarkers for early cancer detection. In this study, we took advantage of an innovative ultrasound (US)-based instrument (SonoWell^®, Inno-Sol srl, Rome, Italy) to treat PC cells in order to promote and amplify the release of molecules, with the aim of identifying novel putative diagnostic PC biomarkers. Methods: Three human pancreatic adenocarcinoma cell lines (T3M-4, Panc02.03, and PaCa-44) and a non-cancerous pancreatic epithelial line (HPanEPic) were subjected to US using the SonoWell instrument. MiRNAs released in the supernatants were profiled by TaqMan-based qRT-PCR microfluidic cards, while proteins were analyzed by antibody arrays. Publicly available datasets of circulating miRNAs in PC patients were also reviewed. Results: Expression levels of 22 miRNAs in T3M-4 cells, 11 in Panc02.03, and 22 in PaCa-44, none of which were identified in the non-cancerous cell line profiling, were increased in the supernatant of US-treated as opposed to control cells. Among the statistically significant miRNAs or miRNAs common to at least two tumor cell lines, the expression levels of miR-155-5p, miR-320a, miR-32-5p, and miR-93-5p were also found to be significantly upregulated in sera from PC patients compared to the results for healthy controls. With regard to proteins released after sonication, several molecules were identified as candidate biomarkers in cancer US supernatants (Beta-2 microglobulin, CA125, CA19-9, CEA, CRP, Galectin-3, TIMP-1, uPA, and VEGF-A). Conclusions: We demonstrated that US-mediated sonoporation can promote and amplify the release of small molecules, miRNAs, and proteins into cell culture supernatants for consideration as putative biomarkers, thus encouraging further studies aimed at directly validating their expression levels in sera/plasma from PC patients and at deepening their role in the treatment of PC. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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15 pages, 1044 KiB

Open AccessArticle

Impact of Long-Term Chemotherapy on Outcomes in Pancreatic Ductal Adenocarcinoma: A Real-World UK Multi-Centre Study

by Umair Mahmood, Joanna Lynch, Simran Kaur Sandhu, Zahir Amin, John Bridgewater, Daniel Hochhauser, Kai-Keen Shiu, Paul Miller, Elizabeth C. Smyth and Khurum Khan

Cancers 2025, 17(11), 1896; https://doi.org/10.3390/cancers17111896 - 5 Jun 2025

Viewed by 387

Abstract

Background: We reviewed outcomes of short and long-term chemotherapy with or without breaks in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: PDAC patients receiving ≥3 chemotherapy cycles between 2019 and 2024 at three institutions were included. Progression-free survival after first-line chemotherapy (PFS1), overall survival [...] Read more.

Background: We reviewed outcomes of short and long-term chemotherapy with or without breaks in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: PDAC patients receiving ≥3 chemotherapy cycles between 2019 and 2024 at three institutions were included. Progression-free survival after first-line chemotherapy (PFS1), overall survival (OS) and best overall response (BOR) to chemotherapy were assessed using the Wilcoxon test, Kaplan–Meier test, and univariate and multivariate Cox regression models. Results: We screened 237 patients, and 135 patients met the study criteria. Among these patients, 25 had resectable disease, and 110 had unresectable/metastatic disease (13% borderline resectable (BRPC), 20% locally advanced (LAPC), 10% localised developing metastases, 57% de novo metastatic). Ten patients (7%) underwent genetic profiling; KRAS aberrations (N = 4), actionable PLAB2/BRCA2/FGFR2 mutations (N = 3), ATM/BRIP1 alteration (N = 1). Two patients were managed with PARP inhibitors after receiving multiple lines of chemotherapy. Median PFS1 and OS were concordant with the published literature, but select patient groups achieved prolonged survival outcomes. Among the 36 BRPC/LAPC patients, we observed >1-year PFS1 in 9 (25%) patients and >2-year OS in 3 (8%) patients. Among the 63 de novo metastatic patients, we observed >1-year PFS1 and >2-year OS in 6 (10%) patients. Among patients with localised disease, smoking history was a poor prognostic factor with respect to OS (p = 0.03). Improved PFS1 and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥3.66 months, and local treatment after first chemotherapy (p < 0.05 for all). Stereotactic body radiotherapy following first-line chemotherapy was delivered in N = 6 (27%) and N = 1 (7%) of patients with LAPC and BRPC, respectively. Chemotherapy interruption duration, but not number, was associated with PFS1 and OS only in the localised cohort (p < 0.05). In patients with de novo metastatic disease, prevalence of type 2 diabetes was adversely associated with OS (p = 0.03). Improved PFS and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥4.37 months, and BOR to it (only in this cohort) (p < 0.05 for all). A favourable OS was associated with >1 line of chemotherapy (p = 0.003). Conclusion: Despite challenges, extended chemotherapy and multiple treatment lines may improve survival, with localised treatments benefiting select patients. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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16 pages, 2789 KiB

Open AccessArticle

The RAGE Inhibitor TTP488 (Azeliragon) Demonstrates Anti-Tumor Activity and Enhances the Efficacy of Radiation Therapy in Pancreatic Cancer Cell Lines

by Kumari Alka, Jacob F. Oyeniyi, Ghulam Mohammad, Yi Zhao, Stephen Marcus and Prakash Chinnaiyan

Cancers 2025, 17(1), 17; https://doi.org/10.3390/cancers17010017 - 24 Dec 2024

Cited by 1 | Viewed by 1266

Abstract

Pancreatic cancer is the third leading cause of cancer-related mortality in the United States, with rising incidence and mortality. The receptor for advanced glycation end products (RAGE) and its ligands significantly contribute to pancreatic cancer progression by enhancing cell proliferation, fostering treatment resistance, [...] Read more.

Pancreatic cancer is the third leading cause of cancer-related mortality in the United States, with rising incidence and mortality. The receptor for advanced glycation end products (RAGE) and its ligands significantly contribute to pancreatic cancer progression by enhancing cell proliferation, fostering treatment resistance, and promoting a pro-tumor microenvironment via activation of the nuclear factor-kappa B (NF-κB) signaling pathways. This study validated pathway activation in human pancreatic cancer and evaluated the therapeutic efficacy of TTP488 (Azeliragon), a small-molecule RAGE inhibitor, alone and in combination with radiation therapy (RT) in preclinical models of pancreatic cancer. Human (Panc1) and murine (Pan02) pancreatic cancer cell lines exhibited elevated levels of RAGE and its ligands compared to normal pancreatic tissue. In vitro, Azeliragon inhibited RAGE-mediated NF-κB activation and ligand-mediated cell proliferation in pancreatic cancer cell lines. Target engagement of Azeliragon was confirmed in vivo, as determined by decreased NF-κB activation. Azeliragon demonstrated significant growth delay in mouse models of pancreatic cancer and additive effects when combined with RT. Additionally, Azeliragon modulated the immune suppressive tumor microenvironment in pancreatic cancer by reducing immunosuppressive cells, including M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells, while enhancing CD8+ T cell infiltration. These findings suggest that Azeliragon, by inhibiting RAGE-mediated signaling and modulating immune response, may serve as an effective anti-cancer agent in pancreatic cancer. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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10 pages, 797 KiB

Open AccessFeature PaperArticle

Obesity Is Associated with Distal Migration of Pancreatic Adenocarcinoma to Body and Tail: A Multi-Center Study

by Wisam Sbeit, Gil Gershovitz, Amir Shahin, Shhady Shhadeh, Mahmoud Salman, Maamoun Basheer and Tawfik Khoury

Cancers 2024, 16(2), 359; https://doi.org/10.3390/cancers16020359 - 14 Jan 2024

Viewed by 1491

Abstract

(1) Background: Pancreatic adenocarcinoma (PAC) is one of the most lethal types of cancer. Most cases of PAC occur in the head of the pancreas. Given the proximity of the pancreatic head to the bile duct, most patients present clinically during early stages [...] Read more.

(1) Background: Pancreatic adenocarcinoma (PAC) is one of the most lethal types of cancer. Most cases of PAC occur in the head of the pancreas. Given the proximity of the pancreatic head to the bile duct, most patients present clinically during early stages of the disease, while distally located PAC could have delayed clinical presentation. (2) Aims: To assess predictors of non-head PAC. (3) Methods: A retrospective multicenter study was conducted, including all patients who had endoscopic ultrasound (EUS) for pancreatic masses and who had histologic confirmation of PAC. (4) Results: Of the 151 patients included, 92 (60.9%) had pancreatic head cancer, and 59 (39.1%) had distal pancreatic cancer. PAC at body was the most common location in the distal PAC group (31 patients (52.5%)). Logistic regression analysis demonstrated a significant association of obesity with distal migration of PAC (OR 4.44, 95% CI 1.15–17.19, p = 0.03), while none of the other assessed parameters showed a significant association. Notably, abdominal pain was more significantly associated with distal PAC vs. head location (OR 2.85, 95% CI 1.32–6.16, p = 0.008). (5) Conclusions: Obesity shows a significant association as a clinical predictor of distal PAC. Further studies are needed to better explore this association. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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21 pages, 4952 KiB

Open AccessArticle

Neutralization of p40 Homodimer and p40 Monomer Leads to Tumor Regression in Patient-Derived Xenograft Mice with Pancreatic Cancer

by Monica Sheinin, Susanta Mondal and Kalipada Pahan

Cancers 2023, 15(24), 5796; https://doi.org/10.3390/cancers15245796 - 11 Dec 2023

Cited by 1 | Viewed by 3374

Abstract

Pancreatic cancer is a highly aggressive cancer with a high mortality rate and limited treatment options. It is the fourth leading cause of cancer in the US, and mortality is rising rapidly, with a 12% relative 5-year survival rate. Early diagnosis remains a [...] Read more.

Pancreatic cancer is a highly aggressive cancer with a high mortality rate and limited treatment options. It is the fourth leading cause of cancer in the US, and mortality is rising rapidly, with a 12% relative 5-year survival rate. Early diagnosis remains a challenge due to vague symptoms, lack of specific biomarkers, and rapid tumor progression. Interleukin-12 (IL-12) is a central cytokine that regulates innate (natural killer cells) and adaptive (cytokine T-lymphocytes) immunity in cancer. We demonstrated that serum levels of IL-12p40 homodimer (p40₂) and p40 monomer (p40) were elevated and that of IL-12 and IL-23 were lowered in pancreatic cancer patients compared to healthy controls. Comparably, human PDAC cells produced greater levels of p40₂ and p40 and lower levels of IL-12 and IL-23 compared to normal pancreatic cells. Notably, neutralization of p40₂ by mAb a3-1d and p40 by mAb a3-3a induced the death of human PDAC cells, but not normal human pancreatic cells. Furthermore, we demonstrated that treatment of PDX mice with p40₂ mAb and p40 mAb resulted in apoptosis and tumor shrinkage. This study illustrates a new role of p40₂ and p40 monomer in pancreatic cancer, highlighting possible approaches against this deadly form of cancer with p40₂ and p40 monomer immunotherapies. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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12 pages, 270 KiB

Open AccessArticle

The Unmet Needs of Pancreatic Cancer Carers Are Associated with Anxiety and Depression in Patients and Carers

by Thi N. T. Huynh, Gunter Hartel, Monika Janda, David Wyld, Neil Merrett, Helen Gooden, Rachel E. Neale and Vanessa L. Beesley

Cancers 2023, 15(22), 5307; https://doi.org/10.3390/cancers15225307 - 7 Nov 2023

Cited by 6 | Viewed by 3345

Abstract

Pancreatic cancer has one of the lowest survival rates, and patients experience debilitating symptoms. Family carers provide essential daily care. This study determined the prevalence of and risk factors for unmet supportive care needs among carers for pancreatic cancer patients and examined which [...] Read more.

Pancreatic cancer has one of the lowest survival rates, and patients experience debilitating symptoms. Family carers provide essential daily care. This study determined the prevalence of and risk factors for unmet supportive care needs among carers for pancreatic cancer patients and examined which carer needs were associated with anxiety and depression in carers and patients. Eighty-four pancreatic cancer patients and their carers were recruited. The carers completed a needs survey (SCNS-P&C). Both carers and patients completed the Hospital Anxiety and Depression Scale. Log binomial regression was used to identify associations between carer needs and anxiety and depression among carers and patients. The top 10 moderate-to-high unmet needs reported by ≥28% of carers were related to healthcare (e.g., discussing concerns with doctors) and information need domains (e.g., information about a patient’s physical needs), plus one other item related to hospital parking. Being male or caring for a patient within 4 months of their diagnosis were associated with greater unmet needs. Some unmet needs, including ‘accessing information about treatments’ and ‘being involved in patient care’, were associated with both carers and patients having anxiety and depression. Carers should be involved in health care consultations and provided with information and opportunities to discuss concerns. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

11 pages, 1074 KiB

Open AccessArticle

Real-Life Results of Palliative Chemotherapy in Metastatic Pancreatic Ductal Adenocarcinoma

by Bianca Varzaru, Razvan A. Iacob, Adina E. Croitoru, Speranta M. Iacob, Cristina E. Radu, Stefania M. Dumitrescu and Cristian Gheorghe

Cancers 2023, 15(13), 3500; https://doi.org/10.3390/cancers15133500 - 5 Jul 2023

Cited by 3 | Viewed by 1671

Abstract

Purpose: To assess the efficacy of FOLFIRINOX(FFX), gemcitabine-based regimens (GB), and gemcitabine monotherapy (Gem) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: This is a retrospective study that included 83 patients with mPDAC treated with first-line chemotherapy (L1) with either FFX, GB [...] Read more.

Purpose: To assess the efficacy of FOLFIRINOX(FFX), gemcitabine-based regimens (GB), and gemcitabine monotherapy (Gem) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: This is a retrospective study that included 83 patients with mPDAC treated with first-line chemotherapy (L1) with either FFX, GB or Gem between 2015 and 2017. Progression-free survival (PFS) for L1 and second-line chemotherapy (L2) (PFS-L1 and PFS-L2) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Median PFS-L1 for FFX, GB and Gem groups was 9 months (95% (Confidence Interval) CI 2.76–15.24), 5 months (95%CI 3.44–6.56), and 5 months (95%CI 3.76–6.24), respectively (p = 0.04). OS was 14 months (95%CI 11.16–16.85), 12 months (95%CI: 9.44–11.56), and 7 months (95%CI: 5.7–8.3) for patients treated with FFX, GB, and Gem, respectively (p = 0.0001). ECOG-PS (0/1) (Hazard Ratio (HR) 6.74, p = 0.002), age > 70 years (HR 0.25, p = 0.04), body tumors (HR 2.8, p = 0.048), CA19–9 > 39 U/mL (HR 0.26, p = 0.02), and neutrophil-to-lymphocyte ratio (NLR) > 4.15 (HR 6.76, p = 0.001) were independent prognostic factors for PFS-L1. Male gender (HR 3.02, p = 0.026), ECOG-PS (0/1) (HR 4.21, p = 0.003), L1 with FFX (HR 0.255, p = 0.007), and NLR > 4.15 (HR 2.65, p = 0.04) were independent prognostic factors of OS. PFS-L2 (HR 6.91, p = 0.013) and OS-L2 (HR 6.95, p = 0.037) were significantly higher in patients first treated with FFX. Conclusions: The OS of patients who receive FFX or GB is comparable. The best PFS-L1 belongs to the FFX group. Male gender, ECOG-PS 0/1, the FFX regimen, and NLR > 4.15 were independent predictors of OS. PFS-L2 and OS-L2 were favorably impacted by L1 with FFX. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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Review

Jump to: Research, Other

23 pages, 1338 KiB

Open AccessReview

Advancing Precision Medicine in PDAC: An Ethical Scoping Review and Call to Action for IHC Implementation

by Lyanne A. Delgado-Coka, Lucia Roa-Peña, Andrew Flescher, Luisa F. Escobar-Hoyos and Kenneth R. Shroyer

Cancers 2025, 17(12), 1899; https://doi.org/10.3390/cancers17121899 - 6 Jun 2025

Viewed by 329

Abstract

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis, prevention, and treatment. Predictive biomarkers offer the potential to revolutionize clinical management, particularly in the preoperative setting, but their implementation requires careful consideration of ethical implications. This scoping review analyzes the ethical landscape of [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in diagnosis, prevention, and treatment. Predictive biomarkers offer the potential to revolutionize clinical management, particularly in the preoperative setting, but their implementation requires careful consideration of ethical implications. This scoping review analyzes the ethical landscape of using immunohistochemistry (IHC) for molecular subtyping in PDAC, focusing on its utility, accessibility, and potential impact on patient care. We conducted a systematic literature search in the PubMed, Scopus and Google Scholar databases (2015–2025) using COVIDENCE, which identified 130 references. Of these, 79 were reviewed in a full-text format, and 9 ultimately met the inclusion criteria for our analysis. IHC offers several advantages as a companion diagnostic tool. It is relatively inexpensive, widely available in most pathology laboratories, and can be readily integrated into existing clinical workflows. This contrasts with more complex molecular subtyping methods, such as gene expression profiling, which can be costly, require specialized equipment and expertise, and may not be readily accessible in all clinical settings. Furthermore, accurate analysis of gene expression requires the localized targeting of individual cells; therefore, digesting the sample for bulk analysis would be less informative than using spatial localization techniques such as IHC. Because biomarker regulation can occur at the level of transcription or translation, protein-level assessment via IHC is often more accurate than mRNA analysis. Standardized IHC protocols for biomarker assessment are therefore essential for translating the molecular subtyping of PDAC into clinically actionable treatment strategies, especially for aggressive subtypes like basal-like tumors. This readily deployable IHC-based approach can optimize therapy selection, maximizing patient benefits and minimizing exposure to ineffective and potentially toxic treatments. This review critically analyzes the ethical dimensions of this method, grounded in the principles of autonomy, beneficence, non-maleficence, and justice. The review urges the medical community to fully utilize the potential of IHC-driven molecular subtyping to improve outcomes in PDAC, while ensuring equitable and responsible access to the benefits of precision oncology for all patients. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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23 pages, 2262 KiB

Open AccessReview

The Role of Nanoparticles in Therapy of Real-World Patients with Pancreatic Cancer: A Scoping Review

by Ioannis Konstantinidis, Sophia Tsokkou, Dimitrios Katsikeros, Paraskevi Chatzikomnitsa, Menelaos Papakonstantinou, Eftychia Liampou, Evdokia Toutziari, Dimitrios Giakoustidis, Petros Bageas, Vasileios Papadopoulos, Alexandros Giakoustidis and Theodora Papamitsou

Cancers 2025, 17(10), 1726; https://doi.org/10.3390/cancers17101726 - 21 May 2025

Viewed by 467

Abstract

Pancreatic cancer (PC) is one of the most aggressive and fatal malignancies worldwide, posing a significant global health challenge due to its high mortality rates, late-stage diagnosis, and limited therapeutic efficacy [...] Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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Graphical abstract

35 pages, 5451 KiB

Open AccessReview

Innate Immunity and Platelets: Unveiling Their Role in Chronic Pancreatitis and Pancreatic Cancer

by Juliane Blümke, Moritz Schameitat, Atul Verma, Celina Limbecker, Elise Arlt, Sonja M. Kessler, Heike Kielstein, Sebastian Krug, Ivonne Bazwinsky-Wutschke and Monika Haemmerle

Cancers 2025, 17(10), 1689; https://doi.org/10.3390/cancers17101689 - 17 May 2025

Viewed by 756

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal forms of cancer, characterized by a highly desmoplastic tumor microenvironment. One main risk factor is chronic pancreatitis (CP). Progression of CP to PDAC is greatly influenced by persistent inflammation promoting genomic instability, acinar–ductal metaplasia, and pancreatic intraepithelial neoplasia (PanIN) formation. Components of the extracellular matrix, including immune cells, can modulate this progression phase. This includes cells of the innate immune system, such as natural killer (NK) cells, macrophages, dendritic cells, mast cells, neutrophils, and myeloid-derived suppressor cells (MDSCs), either promoting or inhibiting tumor growth. On one hand, innate immune cells can trigger inflammatory responses that support tumor progression by releasing cytokines and growth factors, fostering tumor cell proliferation, invasion, and metastasis. On the other hand, they can also activate immune surveillance mechanisms, which can limit tumor development. For example, NK cells are cytotoxic innate lymphoid cells that are able to kill tumor cells, and active dendritic cells are crucial for a functioning anti-tumor immune response. In contrast, mast cells and MDSCs rather support a pro-tumorigenic tumor microenvironment that is additionally sustained by platelets. Once thought to play a role in hemostasis only, platelets are now recognized as key players in inflammation and cancer progression. By releasing cytokines, growth factors, and pro-angiogenic mediators, platelets help shape an immunosuppressive microenvironment that promotes fibrotic remodeling, tumor initiation, progression, metastasis, and immune evasion. Neutrophils and macrophages exist in different functional subtypes that can both act pro- and anti-tumorigenic. Understanding the complex interactions between innate immune cells, platelets, and early precursor lesions, as well as PDAC cells, is crucial for developing new therapeutic approaches that can harness the immune and potentially also the coagulation system to target and eliminate tumors, offering hope for improved patient outcomes. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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25 pages, 1699 KiB

Open AccessReview

From Genes to Environment: Elucidating Pancreatic Carcinogenesis Through Genetically Engineered and Risk Factor-Integrated Mouse Models

by Bin Yan, Anne-Kristin Fritsche, Erik Haußner, Tanvi Vikrant Inamdar, Helmut Laumen, Michael Boettcher, Martin Gericke, Patrick Michl and Jonas Rosendahl

Cancers 2025, 17(10), 1676; https://doi.org/10.3390/cancers17101676 - 15 May 2025

Viewed by 529

Abstract

Pancreatic cancer is characterized by late diagnosis, therapy resistance, and poor prognosis, necessitating the exploration of early carcinogenesis and prevention methods. Preclinical mouse models have evolved from cell line-based to human tumor tissue- or organoid-derived xenografts, now to humanized mouse models and genetically [...] Read more.

Pancreatic cancer is characterized by late diagnosis, therapy resistance, and poor prognosis, necessitating the exploration of early carcinogenesis and prevention methods. Preclinical mouse models have evolved from cell line-based to human tumor tissue- or organoid-derived xenografts, now to humanized mouse models and genetically engineered mouse models (GEMMs). GEMMs, primarily driven by oncogenic Kras mutations and tumor suppressor gene alterations, offer a realistic platform for investigating pancreatic cancer initiation, progression, and metastasis. The incorporation of inducible somatic mutations and CRISPR-Cas9 screening methods has expanded their utility. To better recapitulate tumor initiation triggered by inflammatory cues, common pancreatic risk factors are being integrated into model designs. This approach aims to decipher the role of environmental factors as secondary or parallel triggers of tumor initiation alongside oncogenic burdens. Emerging models exploring pancreatitis, obesity, diabetes, and other risk factors offer significant translational potential. This review describes current mouse models for studying pancreatic carcinogenesis, their combination with inflammatory factors, and their utility in evaluating pathogenesis, providing guidance for selecting the most suitable models for pancreatic cancer research. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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28 pages, 1911 KiB

Open AccessReview

Long Non-Coding RNAs and RNA-Binding Proteins in Pancreatic Cancer Development and Progression

by Pit Preckwinkel, Khursheed Ul Islam Mir, Florian W. Otto, Hend Elrewany, Andrea Sinz, Stefan Hüttelmaier, Nadine Bley and Tony Gutschner

Cancers 2025, 17(10), 1601; https://doi.org/10.3390/cancers17101601 - 8 May 2025

Viewed by 1036

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is responsible for about 467,000 cancer deaths annually. An oftentimes asymptomatic early phase of this disease results in a delayed diagnosis, and patients often present with advanced disease. Current treatment [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is responsible for about 467,000 cancer deaths annually. An oftentimes asymptomatic early phase of this disease results in a delayed diagnosis, and patients often present with advanced disease. Current treatment options have limited survival benefits, and only a minor patient population carries actionable genomic alterations. Hence, innovative personalized treatment strategies that consider molecular, cellular and functional analyses are urgently needed for pancreatic cancer patients. However, the majority of the genetic alterations found in PDAC are currently undruggable, or patients’ response is not as expected. Therefore, non-genomic biomarkers and alternative molecular targets should be considered in order to advance the clinical management of PDAC patients. In line with this, recent gene expression and single-cell transcriptome analyses have identified molecular subtypes and transcriptional cell states that affect disease progression and drug efficiency. In this review, we will introduce long non-coding RNAs (lncRNAs) as well as RNA-binding proteins (RBPs) that are able to modulate the transcriptome of a cell through diverse mechanisms, thereby contributing to disease progression. We will provide a brief overview about the general functions of lncRNAs and RBPs, respectively. Subsequently, we will highlight selected lncRNAs and RBPs that have been shown to play a role in PDAC development, progression and drug response. Finally, we will present strategies aiming to interfere with the expression and function of lncRNAs and RBPs. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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23 pages, 2128 KiB

Open AccessReview

Stromal Cells in Early Inflammation-Related Pancreatic Carcinogenesis—Biology and Its Potential Role in Therapeutic Targeting

by Tina Seidel, Nupur Ohri, Markus Glaß, Yoshiaki Sunami, Lutz P. Müller and Jörg Kleeff

Cancers 2025, 17(9), 1541; https://doi.org/10.3390/cancers17091541 - 1 May 2025

Viewed by 642

Abstract

The stroma of healthy pancreases contains various non-hematopoietic, non-endothelial mesenchymal cells. It is altered by chronic inflammation which in turn is a major contributor to the development of pancreatic adenocarcinoma (PDAC). In PDAC, the stroma plays a decisive and well-investigated role for tumor [...] Read more.

The stroma of healthy pancreases contains various non-hematopoietic, non-endothelial mesenchymal cells. It is altered by chronic inflammation which in turn is a major contributor to the development of pancreatic adenocarcinoma (PDAC). In PDAC, the stroma plays a decisive and well-investigated role for tumor progression and therapy response. This review addresses the central role of stromal cells in the early inflammation-driven development of PDAC. It focuses on major subpopulations of pancreatic mesenchymal cells, i.e., fibroblasts, pancreatic stellate cells, and multipotent stroma cells, particularly their activation and functional alterations upon chronic inflammation including the development of different types of carcinoma-associated fibroblasts. In the second part, the current knowledge on the impact of activated stroma cells on acinar-to-ductal metaplasia and the transition to pancreatic intraepithelial neoplasia is summarized. Finally, putative strategies to target stroma cells and their signaling in early pancreatic carcinogenesis are reflected. In summary, the current data show that the activation of pancreatic stroma cells and the resulting fibrotic changes has pro- and anti-carcinogenetic effects but, overall, creates a carcinogenesis-promoting microenvironment. However, this is a dynamic process and the therapeutic targeting of specific pathways and cells requires in-depth knowledge of the molecular interplay of various cell types. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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13 pages, 1137 KiB

Open AccessReview

Exploring the Horizon: Anti-Fibroblast Growth Factor Receptor Therapy in Pancreatic Cancer with Aberrant Fibroblast Growth Factor Receptor Expression—A Scoping Review

by Elena Orlandi, Massimo Guasconi, Stefano Vecchia, Serena Trubini, Mario Giuffrida, Manuela Proietto, Elisa Anselmi, Patrizio Capelli and Andrea Romboli

Cancers 2024, 16(16), 2912; https://doi.org/10.3390/cancers16162912 - 22 Aug 2024

Viewed by 1481

Abstract

Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and [...] Read more.

Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and clinical studies on FGFR (Fibroblast Growth Factor Receptor) inhibitors, including tyrosine kinase inhibitors (TKIs) and FGFR-specific inhibitors, in pancreatic cancer with FGFR alterations. We included studies analyzing efficacy, safety, and survival outcomes in various populations. A comprehensive search across major databases identified 73 relevant studies: 32 preclinical, 16 clinical, and 25 from gray literature. The clinical trials focused primarily on efficacy (20 studies) and safety (14 studies), with fewer studies addressing survival outcomes. FGFR1 was the most studied alteration, followed by FGFR2 and FGFR4. Although FGFR alterations are relatively rare in pancreatic cancer, the available data, including promising real-life outcomes, suggest significant potential for FGFR inhibitors. However, more extensive research is needed to identify the correct genetic drivers and gather robust survival data. Ongoing and future trials are expected to provide more comprehensive insights, potentially leading to improved targeted therapies for pancreatic cancer patients with FGFR alterations. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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26 pages, 1189 KiB

Open AccessReview

Gaps and Opportunities in the Diagnosis and Treatment of Pancreatic Cancer

by Miłosz Caban and Ewa Małecka-Wojciesko

Cancers 2023, 15(23), 5577; https://doi.org/10.3390/cancers15235577 - 25 Nov 2023

Cited by 11 | Viewed by 3470

Abstract

Pancreatic cancer is one of the leading causes off cancer-related deaths globally. In Europe, this type of cancer has the lowest survival rate of all cancers. A majority of patients have unresectable or even metastatic disease. In addition, actual therapeutic options are not [...] Read more.

Pancreatic cancer is one of the leading causes off cancer-related deaths globally. In Europe, this type of cancer has the lowest survival rate of all cancers. A majority of patients have unresectable or even metastatic disease. In addition, actual therapeutic options are not curative, and surgical treatment is associated with high post-operative morbidity and a lack of uniform translation of surgical success into long-term survival. Moreover, there is no screening for the general population which is recommended, and the overall poor prognosis in pancreatic cancer is related to late clinical detection. Therefore, early diagnosis and early treatment of pancreatic cancer are particularly critical. In this review, we summarize the most significant gaps and opportunities in the diagnosis and treatment of pancreatic cancer to emphasize need for improvement of early detection and the therapeutic efficacy of the available treatment for this cancer. Novel, inclusive, and intentional research is needed to produce improvements in pancreatic cancer in mm the world. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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15 pages, 1347 KiB

Open AccessReview

Pancreatic Exocrine Insufficiency and the Gut Microbiome in Pancreatic Cancer: A Target for Future Diagnostic Tests and Therapies?

by James M. Halle-Smith, Lewis A. Hall, Sarah F. Powell-Brett, Nabeel Merali, Adam E. Frampton, Andrew D. Beggs, Paul Moss and Keith J. Roberts

Cancers 2023, 15(21), 5140; https://doi.org/10.3390/cancers15215140 - 25 Oct 2023

Cited by 2 | Viewed by 3035

Abstract

Pancreatic exocrine insufficiency (PEI) is common amongst pancreatic cancer patients and is associated with poorer treatment outcomes. Pancreatic enzyme replacement therapy (PERT) is known to improve outcomes in pancreatic cancer, but the mechanisms are not fully understood. The aim of this narrative literature [...] Read more.

Pancreatic exocrine insufficiency (PEI) is common amongst pancreatic cancer patients and is associated with poorer treatment outcomes. Pancreatic enzyme replacement therapy (PERT) is known to improve outcomes in pancreatic cancer, but the mechanisms are not fully understood. The aim of this narrative literature review is to summarise the current evidence linking PEI with microbiome dysbiosis, assess how microbiome composition may be impacted by PERT treatment, and look towards possible future diagnostic and therapeutic targets in this area. Early evidence in the literature reveals that there are complex mechanisms by which pancreatic secretions modulate the gut microbiome, so when these are disturbed, as in PEI, gut microbiome dysbiosis occurs. PERT has been shown to return the gut microbiome towards normal, so called rebiosis, in animal studies. Gut microbiome dysbiosis has multiple downstream effects in pancreatic cancer such as modulation of the immune response and the response to chemotherapeutic agents. It therefore represents a possible future target for future therapies. In conclusion, it is likely that the gut microbiome of pancreatic cancer patients with PEI exhibits dysbiosis and that this may potentially be reversible with PERT. However, further human studies are required to determine if this is indeed the case. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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14 pages, 263 KiB

Open AccessPerspective

Exercise Guidelines in Pancreatic Cancer Based on the Dietz Model

by Philip J. Chang, Andrew E. Hendifar, Gillian Gresham, An Ngo-Huang, Paul E. Oberstein, Nathan Parker and Andrew L. Coveler

Cancers 2025, 17(4), 630; https://doi.org/10.3390/cancers17040630 - 13 Feb 2025

Viewed by 1047

Abstract

Pancreatic and gastrointestinal cancers are associated with debility, frailty, and chemotherapy regiments with significant toxicity. Practical exercise guidelines to combat these ailments and optimize functional status are lacking. We present a model for exercise for these cancers based on the Dietz framework for [...] Read more.

Pancreatic and gastrointestinal cancers are associated with debility, frailty, and chemotherapy regiments with significant toxicity. Practical exercise guidelines to combat these ailments and optimize functional status are lacking. We present a model for exercise for these cancers based on the Dietz framework for rehabilitation in cancer. The Dietz framework for rehabilitation describes four phases of rehabilitation including preventative (prehabilitation), restorative, supportive, and palliative. We present practical guidelines for exercise at each phase. Prehabilitation seeks to optimize functional performance typically prior to surgical resection and may occur concurrently with neoadjuvant therapy. Restorative rehabilitation occurs following the development of a physical deficit such as after surgery and may utilize skilled therapies in the inpatient, subacute, outpatient, and home settings to address functional impairments. Supportive rehabilitation occurs during stable disease or remission and depends on the frequent monitoring of functional status and particularly the development of chemotherapy-induced neuropathy to ensure timely exercise interventions. Palliative rehabilitation occurs at the end stage of life and shifts to a focus on patient comfort and safety. Exercise is a critical component of treatment in cancer demonstrating numerous quality-of-life benefits. The customization of exercise recommendations to individual patients based on their functional status and phase in treatment is essential for safety and adherence. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

13 pages, 1833 KiB

Open AccessSystematic Review

Gestational Diabetes Mellitus and Its Correlation in the Development of Pancreatic Cancer: A 10-Year Systematic Review

by Sophia Tsokkou, Ioannis Konstantinidis, Maria-Nefeli Georgaki, Dimitrios Kavvadas, Kyriaki Papadopoulou, Antonios Keramas, Antonia Sioga, Theodora Papamitsou and Sofia Karachrysafi

Cancers 2024, 16(10), 1840; https://doi.org/10.3390/cancers16101840 - 11 May 2024

Cited by 4 | Viewed by 2275

Abstract

Purpose: Pancreatic cancer (PC) is a fatal malignancy with an aggressive course derived from the cells of pancreatic tissue. Gestational diabetes mellitus (GDM) is a state of spontaneous hyperglycemia occurring during gestation and has been suggested as a risk factor PC. Women with [...] Read more.

Purpose: Pancreatic cancer (PC) is a fatal malignancy with an aggressive course derived from the cells of pancreatic tissue. Gestational diabetes mellitus (GDM) is a state of spontaneous hyperglycemia occurring during gestation and has been suggested as a risk factor PC. Women with a history of GDM revealed a risk rate of 7.1% for the development of PC. The current systematic review aims to investigate the correlation between GDM and the degree to the prevalence of PC. Methodology: For this systematic review, the PICO model was prepared to construct and outline the exact questions of the study, a PRISMA flow diagram was prepared and quality assessment was conducted using the Newcastle Ottawa Scale (NOS) for Cohort Studies, the NIH Quality Assessment Tool-Criteria for Case Reports and the Cochrane quality assessment tool for Systematic Reviews and Meta-analysis studies. Result: A total of eight articles were retrieved from the main databases, and a table was created to summarize the information found. Even though the data found were limited, the quality assessment performed revealed that the articles were of high validity. Conclusions: It can be concluded that GDM has an association with the development of PC and can be considered as a risk factor. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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