scholarly journals WNT Ligand Dependencies in Pancreatic Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Kristina Y. Aguilera ◽  
David W. Dawson
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Wnt Signaling ◽  
Transcriptional Activity ◽  
Wnt Pathway ◽  
Cellular Proliferation ◽  
Ductal Adenocarcinoma ◽  
Potential Utility ◽  
Therapeutic Approaches ◽  
Pharmacologic Inhibitors

WNT signaling promotes the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) through wide-ranging effects on cellular proliferation, survival, differentiation, stemness, and tumor microenvironment. Of therapeutic interest is a genetically defined subset of PDAC known to have increased WNT/β-catenin transcriptional activity, growth dependency on WNT ligand signaling, and response to pharmacologic inhibitors of the WNT pathway. Here we review mechanisms underlying WNT ligand addiction in pancreatic tumorigenesis, as well as the potential utility of therapeutic approaches that functionally antagonize WNT ligand secretion or frizzled receptor binding.

scholarly journals Pancreatic Cancer Signaling Pathways, Genetic Alterations, and Tumor Microenvironment: The Barriers Affecting the Method of Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 373
Author(s):  
Darya Javadrashid ◽  
Amir Baghbanzadeh ◽  
Afshin Derakhshani ◽  
Patrizia Leone ◽  
Nicola Silvestris ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Therapeutic Strategy ◽  
Genetic Alterations ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Approaches ◽  
Ras Mutation ◽  
Direct Targeting

Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system’s role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment.

scholarly journals Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Wenting Du ◽  
Marina Pasca di Magliano ◽  
Yaqing Zhang
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Immune Suppression ◽  
Therapeutic Potential ◽  
Molecular Networks ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Approaches ◽  
Cell Plasticity ◽  
Immunosuppressive Microenvironment ◽  
Cellular Components

The stroma-rich, immunosuppressive microenvironment is a hallmark of pancreatic ductal adenocarcinoma (PDA). Tumor cells and other cellular components of the tumor microenvironment, such as cancer associated fibroblasts, CD4+ T cells and myeloid cells, are linked by a web of interactions. Their crosstalk not only results in immune evasion of PDA, but also contributes to pancreatic cancer cell plasticity, invasiveness, metastasis, chemo-resistance, immunotherapy-resistance and radiotherapy-resistance. In this review, we characterize several prevalent populations of stromal cells in the PDA microenvironment and describe how the crosstalk among them drives and maintains immune suppression. We also summarize therapeutic approaches to target the stroma. With a better understanding of the complex cellular and molecular networks in PDA, strategies aimed at sensitizing PDA to chemotherapy or immunotherapy through re-programing the tumor microenvironment can be designed, and in turn lead to improved clinical treatment for pancreatic cancer patients.

scholarly journals The Immune Microenvironment in Pancreatic Cancer

2020 ◽  
Vol 21 (19) ◽  
pp. 7307 ◽  
Author(s):  
Magdalena Huber ◽  
Corinna U. Brehm ◽  
Thomas M. Gress ◽  
Malte Buchholz ◽  
Bilal Alashkar Alhamwe ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Stroma ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Cellular Interactions ◽  
Therapeutic Approaches ◽  
Immune Microenvironment ◽  
Cellular Immune

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care.

scholarly journals The Tumor Microenvironment of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3076
Author(s):  
Eva Karamitopoulou
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Incidence Rates ◽  
Ductal Adenocarcinoma ◽  
Dismal Prognosis ◽  
The Future ◽  
Rising Incidence

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis along with rising incidence rates and will be responsible for many cancer deaths in the future [...]

Inhibition of Wnt Pathway Signaling by Thalidomide and Revlimid: Studies in a Drosophila Model System.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3356-3356
Author(s):  
A. Keith Stewart ◽  
Yuan Xiao Zhu ◽  
Maryan Yahyapour ◽  
Armen Manoukian ◽  
Sam E. Scanga
Keyword(s):  
Wnt Signaling ◽  
Cell Lines ◽  
Wnt Pathway ◽  
High Throughput Sequencing ◽  
Cellular Proliferation ◽  
Wnt Signaling Pathway ◽  
Myeloma Cell ◽  
Lacz Expression ◽  
Western Blots ◽  
Drosophila Model

Abstract High throughput sequencing, gene expression profiling and protein biochemistry in myeloma have all consistently revealed elevated expression of wnt signaling pathways in malignant plasma cells. Indeed, downregulation of the Wnt pathway in myeloma cells has recently been shown to inhibit myeloma cellular proliferation. Preliminary pharmacogenomic studies have also suggested that hyperactivation of the wnt signaling antagonist DKK-1 is associated with response to the immunomodulators thalidomide and revlimid. The mechanism of action for these therapeutically active drugs is however by no means clear as multiple biologic consequences of treatment have been proposed. We report here use of a drosophila model to examine wnt signaling inhibition by these pharmaceuticals. We employed a unique drosophila larval imaginal disc culture system in which wnt pathway activity is monitored through control of LacZ expression by the distalless promoter. In this system 10uM of both thalidomide and revlimid reproducibly inhibit lacZ expression when compared with vehicle controls. Western blots of larva confirmed downregulation of expression of armadillo (the drosophila b-catenin homologue) by both drugs but particularly revlimid. Lithium Chloride is an inhibitor of the drosphila GSK3b homologue shaggy and thus mimics wnt signaling by stabilizing b-catenin. The effect of Lithium could not be overcome by thalidomide or revlimid indicating that the action of these drugs is upstream of shaggy (or GSK3). Next we employed a fly transgenic for wingless which is embryonic lethal. By adding either drug to larval culture medium the lethality of wingless expression was reversed. Indeed drosophila embryos fed thalidomide exhibited developmental plate abnormalities. We next sought evidence that similar effects were evident in revlimid treated human myeloma. As previously reported most myeloma cell lines studied expressed b-catenin and this protein was downregulated by revlimid treatment of human myeloma cell lines co-incident with inhibition of growth as measured by MTT assay. We sought, but failed to find evidence of up-regulation of the wnt signaling pathway antagonist DKK-1 using an ELISA assay on pre and post treatment serum samples in patients responding to thalidomide.The implications of wnt signaling inhibition as a primary or secondary readout of therapeutic efficiency in MM may be of substantial importance in subsequent design of drug therapies or combination therapies.

scholarly journals Tumor cross-talk networks promote growth and support immune evasion in pancreatic cancer

2018 ◽  
Vol 315 (1) ◽  
pp. G27-G35 ◽  
Author(s):  
Christopher J. Halbrook ◽  
Marina Pasca di Magliano ◽  
Costas A. Lyssiotis
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Immune Evasion ◽  
Cross Talk ◽  
Tissue Repair ◽  
Ductal Adenocarcinoma ◽  
Normal Tissues ◽  
Pancreatic Cancer Cells ◽  
Key Driver ◽  
Tumor Maintenance

In the event of an injury, normal tissues exit quiescent homeostasis and rapidly engage a complex stromal and immune program. These tissue repair responses are hijacked and become dysregulated in carcinogenesis to form a growth-supportive tumor microenvironment. In pancreatic ductal adenocarcinoma (PDA), which remains one of the deadliest major cancers, the microenvironment is a key driver of tumor maintenance that impedes many avenues of therapy. In this review, we outline recent efforts made to uncover the microenvironmental cross-talk mechanisms that support pancreatic cancer cells, and we detail the strategies that have been undertaken to help overcome these barriers.

scholarly journals Kallikrein-Related Peptidase 6 Is Associated with the Tumour Microenvironment of Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3969
Author(s):  
Juliana B. Candido ◽  
Oscar Maiques ◽  
Melanie Boxberg ◽  
Verena Kast ◽  
Eleonora Peerani ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Standard Of Care ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Approaches ◽  
Novel Treatments ◽  
Pancreatic Cancer Cells ◽  
Invasive Tumour ◽  
Mrna And Protein Expression

As cancer-associated factors, kallikrein-related peptidases (KLKs) are components of the tumour microenvironment, which represents a rich substrate repertoire, and considered attractive targets for the development of novel treatments. Standard-of-care therapy of pancreatic cancer shows unsatisfactory results, indicating the need for alternative therapeutic approaches. We aimed to investigate the expression of KLKs in pancreatic cancer and to inhibit the function of KLK6 in pancreatic cancer cells. KLK6, KLK7, KLK8, KLK10 and KLK11 were coexpressed and upregulated in tissues from pancreatic cancer patients compared to normal pancreas. Their high expression levels correlated with each other and were linked to shorter survival compared to low KLK levels. We then validated KLK6 mRNA and protein expression in patient-derived tissues and pancreatic cancer cells. Coexpression of KLK6 with KRT19, αSMA or CD68 was independent of tumour stage, while KLK6 was coexpressed with KRT19 and CD68 in the invasive tumour area. High KLK6 levels in tumour and CD68+ cells were linked to shorter survival. KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.

scholarly journals WNT and β-Catenin in Cancer: Genes and Therapy

2020 ◽  
Vol 4 (1) ◽  
pp. 177-196 ◽  
Author(s):  
Rene Jackstadt ◽  
Michael Charles Hodder ◽  
Owen James Sansom
Keyword(s):  
Tumor Microenvironment ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Pathway ◽  
Therapeutic Strategy ◽  
Wnt Signaling Pathway ◽  
Therapeutic Strategies ◽  
Tissue Homeostasis ◽  
Cancer Genes

The WNT pathway is a pleiotropic signaling pathway that controls developmental processes, tissue homeostasis, and cancer. The WNT pathway is commonly mutated in many cancers, leading to widespread research into the role of WNT signaling in carcinogenesis. Understanding which cancers are reliant upon WNT activation and which components of the WNT signaling pathway are mutated is paramount to advancing therapeutic strategies. In addition, building holistic insights into the role of WNT signaling in not only tumor cells but also the tumor microenvironment is a vital area of research and may be a promising therapeutic strategy in multiple immunologically inert cancers. Novel compounds aimed at modulating the WNT signaling pathway using diverse mechanisms are currently under investigation in preclinical/early clinical studies. Here, we review how the WNT pathway is activated in multiple cancers and discuss current strategies to target aberrant WNT signaling.

scholarly journals Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hong-Bo Li ◽  
Zi-Han Yang ◽  
Qing-Qu Guo
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Immune Effector ◽  
Effector Cells ◽  
Pathological Subtype

AbstractPancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting.

Nanomedicine in Pancreatic Cancer: A New Hope for Treatment

2020 ◽  
Vol 21 (15) ◽  
pp. 1580-1592
Author(s):  
Pablo Redruello ◽  
Gloria Perazzoli ◽  
Ana Cepero ◽  
Francisco Quiñonero ◽  
Cristina Mesas ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Side Effects ◽  
Tumor Microenvironment ◽  
Chemotherapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Antitumor Drugs ◽  
Chemotherapeutic Drugs ◽  
Comprehensive Understanding ◽  
Advanced Stages

Pancreatic ductal adenocarcinoma (PDA) has one of the worst prognosis and higher mortality among most cancers. The diagnosis of PDA is frequently delayed due to a lack of specific biomarkers, and the efficacy of current chemotherapeutic drugs is limited. Moreover, chemotherapy is generally applied in advanced stages, where metastatic spread has already occurred. Nanotechnologybased systems are allowing to advance in the diagnosis and treatment of PDA. New nanoformulations have shown to improve the activity of conventional chemotherapeutic agents, such as gemcitabine, and new antitumor drugs, protecting them from degradation, improving their selectivity, solubility and bioavailability, and reducing their side effects. Moreover, the design of nanocarriers represents a new way to overcome drug resistance, which requires a comprehensive understanding of the tumor microenvironment of PDA. This article reviews the current perspectives, based on nanomedicine, to address the limitations of pancreatic cancer treatment, and the futures lines of research to progress in the control of this disease.

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