Transportome Malfunctions and the Hallmarks of Pancreatic Cancer

Ling, Qi; Kalthoff, Holger

doi:10.1007/112_2020_20

Cited by 11 publications

(8 citation statements)

References 106 publications

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“…Reviews from recent years on the role of ion channels in cancer ( Djamgoz et al, 2014 ; Klumpp et al, 2018 ; Prevarskaya et al, 2018 ; Bulk et al, 2020 ; Ling and Kalthoff, 2020 ; Schnipper et al, 2020 ) predominantly focused on how ion channels shape the aggressive cancer cell behavior. However, cancer must be viewed as a complex tissue composed of different cell types.…”

Section: Introductionmentioning

confidence: 99%

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

et al. 2021

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Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the “hallmarks of cancer.” Their expression is dysregulated in cancer, and they are “misused” to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same “profibrotic” ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

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Section: Introductionmentioning

confidence: 99%

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

et al. 2021

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“…In some pancreatic cancers, tumor suppressor or DNA repair genes (such as CDKN2A, CDH1 and MLH1) are found to be silenced by methylation [16]. The overexpressions of microRNAs in pancreatic cancer have also been revealed, which seemed to participate in pancreatic neoplastic development [39][40][41][42][43][44].…”

Section: Genetic Alterations During Pancreatic Tumorigenesismentioning

confidence: 99%

A comprehensive review of pancreatic cancer and its therapeutic challenges

Jiang

Fagman

et al. 2022

Aging

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Pancreatic cancer is a devastating and lethal human malignancy with no curable chemo-treatments available thus far. More than 90% of pancreatic tumors are formed from ductal epithelium as pancreatic ductal adenocarcinoma (PDAC), which often accompany with the expression of mutant K-ras. The incidences of pancreatic cancer are expected to increase rapidly worldwide in the near future, due to environmental pollution, obesity epidemics and etc. The dismal prognosis of this malignancy is contributed to its susceptibility to tumor micro-metastasis from inception and the lack of methods to detect precursor lesions at very early stages of the onset until clinical symptoms occur. In recent years, basic and clinical studies have been making promising progresses for discovering markers to determine the subtypes or stages of this malignancy, which allow effectively implementing personalized therapeutic interventions. The purpose of this review is to discuss the existing knowledge of the molecular mechanisms of pancreatic cancer and the current state of treatment options with the emphasis on targeting therapeutic approaches. The specific focuses are on the molecular mechanisms of the disease, identifications of drug resistance, establishment of immune escaping mechanisms as well as potential of targeting identified pathways in combinations with existing chemo-drugs.www.aging-us.com AGINGpancreatic cancer risk and onset. The majority of the incidences of pancreatic cancer occur sporadically and the disease is often accompanied with genetic abnormalities in somatic cells. Studies have indicated that unlike familial cancer syndromes for gastrointestine/colon or breast, pancreatic cancer has very low penetrance with less than 10% of the cases to be linked to a familial setting [3,4]. Among many genetic lesions detected in pancreatic cancer, active mutant K-ras is one that occurs in early stages of pancreatic tumorigenesis, followed by inactivation of several tumor suppressors, including p53, p16 INK4a , and others (such as SMAD4/DPC4, MLH1, LKB1, PRSS1, and BRCA2) [3,4].

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“…Then a strong correlation between metabolic and Collisson’s subtype was discovered. The relationship between the influence of the microbiota on metabolism and the different genetic subtypes of PDAC deserves further discussion ( 113 ). A study found that in KPC mice and PDAC patients, serum polyamine concentrations were significantly increased.…”

Section: Pancreas-related Microbial Metabolism and Pancreatic Cancermentioning

confidence: 99%

Research Progress of Pancreas-Related Microorganisms and Pancreatic Cancer

Zhang

et al. 2021

Front. Oncol.

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Pancreatic cancer is one of the most common digestive system cancers. Early diagnosis is difficult owing to the lack of specific symptoms and reliable biomarkers. The cause of pancreatic cancer remains ambiguous. Smoking, drinking, new-onset diabetes, and chronic pancreatitis have been proven to be associated with the occurrence of pancreatic cancer. In recent years, a large number of studies have clarified that a variety of microorganisms colonized in pancreatic cancer tissues are also closely related to the occurrence and development of pancreatic cancer, and the specific mechanisms include inflammatory induction, immune regulation, metabolism, and microenvironment changes caused by microorganism. The mechanism of action of the pancreatic colonized microbiome in the tumor microenvironment, as well as immunotherapy approaches require further study in order to find more evidence to explain the complex relationship between the pancreatic colonized microbiome and PDAC. Relevant studies targeting the microbiome may provide insight into the mechanisms of PDAC development and progression, improving treatment effectiveness and overall patient prognosis. In this article, we focus on the research relating to the microorganisms colonized in pancreatic cancer tissues, including viruses, bacteria, and fungi. We also highlight the microbial diversity in the occurrence, invasion, metastasis, treatment, and prognosis of pancreatic cancer in order to elucidate its significance in the early diagnosis and new therapeutic treatment of pancreatic cancer, which urgently need to be improved in clinical practice. The elimination or increase in diversity of the pancreatic microbiome is beneficial for prolonging the survival of PDAC patients, improving the response to chemotherapy drugs, and reducing tumor burden. The colonization of microorganisms in the pancreas may become a new hotspot in the diagnosis and treatment of pancreatic cancer.

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Transportome Malfunctions and the Hallmarks of Pancreatic Cancer

Cited by 11 publications

References 106 publications

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

A comprehensive review of pancreatic cancer and its therapeutic challenges

Research Progress of Pancreas-Related Microorganisms and Pancreatic Cancer

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