Mechanism and Treatment for Pancreatic Cancer Metastases

Editorial

Frontiers in Oncology

Editorial: Mechanism and Treatment for Pancreatic Cancer Metastases

Wenyi Guo

Dong Wu

Jianwei Xu

and

Lei Wang

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Editors

Impact

Based on the ENCODE project approximately 35% of human genes encode proteins and the remaining 65% of them encode noncoding RNA that is shown in the figure.

Review

15 March 2024

The roles of lncRNAs and miRNAs in pancreatic cancer: a focus on cancer development and progression and their roles as potential biomarkers

Somayeh Jafari

, 5 more and

Gholamreza Anani Sarab

Pancreatic ductal adenocarcinoma (PDAC) is among the most penetrative malignancies affecting humans, with mounting incidence prevalence worldwide. This cancer is usually not diagnosed in the early stages. There is also no effective therapy against PDAC, and most patients have chemo-resistance. The combination of these factors causes PDAC to have a poor prognosis, and often patients do not live longer than six months. Because of the failure of conventional therapies, the identification of key biomarkers is crucial in the early diagnosis, treatment, and prognosis of pancreatic cancer. 65% of the human genome encodes ncRNAs. There are different types of ncRNAs that are classified based on their sequence lengths and functions. They play a vital role in replication, transcription, translation, and epigenetic regulation. They also participate in some cellular processes, such as proliferation, differentiation, metabolism, and apoptosis. The roles of ncRNAs as tumor suppressors or oncogenes in the growth of tumors in a variety of tissues, including the pancreas, have been demonstrated in several studies. This study discusses the key roles of some lncRNAs and miRNAs in the growth and advancement of pancreatic carcinoma. Because they are involved not only in the premature identification, chemo-resistance and prognostication, also their roles as potential biomarkers for better management of PDAC patients.

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Sensory neurons secrete CGRP, which acts through the RAMP1 signaling pathway, playing a role in both innate and adaptive inflammatory responses. Upon activation of the RAMP1 receptor, CGRP causes macrophages to release the anti-inflammatory cytokine interleukin (IL)-10, resulting in a reduction of effector CD8+ T lymphocytes. Adrenergic stress from sympathetic nerves leads to the release of norepinephrine and epinephrine, which promote the recruitment of immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) to the Tumor Microenvironment (TME). This prevents an effective anti-tumor immune response, facilitating further cancer growth and progression. Some nerve fibers can express immune checkpoint molecules, such as programmed death ligand 1 (PD-L1), which, upon interacting with programmed cell death protein 1 (PD-1), leads to exhaustion of CD8+ T cells in the TME, thereby inhibiting the anti-tumor immune response. Acetylcholine can directly inhibit the production of IFN-γ by CD8+ T cells and promote the shift from Th1 to Th2. Schwann cells (SCs) release chemokine (C-C motif) ligand 2 (CCL2), leading to chemotaxis and specialization of immunosuppressive M2 macrophages. Furthermore, SCs promote the recruitment and immunosuppressive function of myeloid-derived suppressor cells (MDSCs), contributing to cancer progression.

Review

19 March 2024

Periampullary cancer and neurological interactions: current understanding and future research directions

Yuchen Wang

, 3 more and

Xifeng Fu

2,203 views

1 citations

Original Research

05 February 2024

Construction and validation of a RARRES3-based prognostic signature related to the specific immune microenvironment of pancreatic cancer

Yimeng Sun

, 4 more and

Yu Fan

Background: Tumor immune microenvironment (TiME) is prognostically instructive in Pancreatic adenocarcinoma (PAAD). However, the potential value of TiME-related genes in the individualized immunotherapy of PAAD has not been clarified.

Methods: Correlation between Immune-Related Genes (IRGs) and immune-related transcription factors (TFs) was performed to prove the immune correlation of selected genes. Immune-related molecular subtypes were identified by consensus clustering. The TiME-score, an immune microenvironment-related prognostic signature for PAAD, was constructed using minimum absolute contraction and selection operator regression (Lasso-Cox). The International Cancer Genome Consortium (ICGC) dataset validated the reliability of TiME-score as external validation. Single-cell samples from GSE197177 confirmed microenvironment differences of TiME-score hub genes between tumor and its paracancer tissues. Then, RARRES3, a hub gene in TiME-score, was further analyzed about its upstream TP53 mutation and the specific immune landscape of itself in transcriptome and Single-cell level. Eventually, TiME-score were validated in different therapeutic cohorts of PAAD mice models.

Results: A 14-genes PAAD immune-related risk signature, TiME-score, was constructed based on IRGs. The differences of TiME-score hub genes in single-cell samples of PAAD cancer tissues and adjacent tissues were consistent with the transcriptome. Single-cell samples of cancer tissues showed more pronounced immune cell infiltration. The upstream mutation factor TP53 of RARRES3 was significantly enriched in immune-related biological processes. High RARRES3 expression was correlated with a worse prognosis and high macrophages M1 infiltration. Additionally, the immunohistochemistry of hub genes AGT, DEFB1, GH1, IL20RB, and TRAF3 in different treatment cohorts of mice PAAD models were consistent with the predicted results. The combination of immunotherapy, chemotherapy and targeted therapy has shown significantly better therapeutic effects than single drug therapy in PAAD.

Conclusion: TiME-score, as a prognostic signature related to PAAD-specific immune microenvironment constructed based on RARRES3, has predictive value for prognosis and the potential to guide individualized immunotherapy for PAAD patients.

1,877 views

2 citations

(A) At BM diagnosis: large left anterior frontal tumor in contact with the left optic nerve and perilesional edema. (B) After surgery: left fronto-orbital and dorsolateral ablation site without intraparenchymal enhancement. (C) At first brain recurrence: left frontal nodular meningeal tissue lesion (left) and new right inferior frontal enhanced nodular lesion with meningeal implantation (right). (D) At second brain recurrence: large left temporopolar and frontobasal lesion with significant perilesional edema.

Original Research

08 January 2024

Management and outcomes of brain metastases from pancreatic adenocarcinoma: a pooled analysis and literature review

Etienne Gouton

, 8 more and

Brice Chanez

1,657 views

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Original Research

07 December 2023

Primary squamous cell carcinoma of the pancreas: an update on a rare neoplasm from the SEER database

Jacob A. Ford

, 3 more and

Aidan M. Burke

Introduction: Pancreatic squamous cell carcinoma is a rare type of pancreatic cancer of ductal origin, composing an estimated 0.5 - 5% of pancreatic ductal malignancies. As a result, epidemiology, treatment options, and associated outcomes are poorly understood and understudied. Our aim was two-fold: to evaluate demographic trends and analyze overall survival (OS) associated with different treatment modalities for this rare malignancy.

Methods: Patients with pancreatic squamous cell carcinoma diagnosed between 1992 and 2019 were eligible and reviewed utilizing the Surveillance, Epidemiology, and End Results Registry (SEER) database. Data was analyzed using SPSS and python packages lifelines and pandas. Variables of interest included stage at diagnosis as well as the receipt of surgery, radiotherapy, and/or chemotherapy. Five-year OS curves were analyzed using Kaplan-Meier probability stratified by treatment modality.

Results: Of 342 cases of pancreatic squamous cell carcinoma, 170 (49.7%) were females and 172 (50.3%) were males. 72 (21.1%) of patients received radiotherapy, 123 (35.9%) patients received chemotherapy, and 47 (13.7%) received surgery. Patients who were diagnosed under the age of 50 had prolonged survival time compared to those diagnosed over the age of 50 (12 vs 8 months, respectively, p < 0.001). This trend was evident despite the lack of a significant association between age at diagnosis and presence of metastases (p = 0.524). The median OS was 3 months for the entire cohort and there was a significant difference in median survival time noted across treatment modalities: OS was prolonged in those receiving surgery compared to those receiving chemotherapy or radiotherapy alone (30 vs 2 months, respectively, (p<0.001)). Receipt of radiotherapy was not associated with a significant difference in OS compared to those who did not receive radiotherapy.

Conclusion: Pancreatic squamous cell carcinoma is a rare subtype of pancreatic cancer and typically portends a poor prognosis. As demonstrated by our study, surgery offers prolonged overall survival compared to other treatment modalities. Age at diagnosis and presence of metastatic disease are also important prognostic factors likely related to patients‘ ability to tolerate surgery or physician willingness to offer surgery. Given the importance of surgery on outcomes, it may be reasonable to offer it in the oligometastatic setting in patients who are otherwise a good candidate. Future research on larger cohorts is warranted to investigate the role that modality selection plays in overall survival rates in this understudied malignancy.

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4 citations