Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment

Sáinz, Bruno; Alcalá, Sonia; García, Elena; Sanchez-Ripoll, Yolanda; Azevedo, Mafalda; Cioffi, Michèle; Tatari, Marianthi; Miranda-Lorenzo, Irene; Hidalgo, Manuel; Gómez‐López, Gonzalo; Cañamero, Marta; Erkan, Mert; Kleeff, Jörg; García‐Silva, Susana; Sancho, Patricia; Hermann, Patrick C.; Heeschen, Christopher

doi:10.1136/gutjnl-2014-308935

Cited by 121 publications

(91 citation statements)

References 58 publications

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“…When MSCs are cultured with lung cancer cells, sphere formation and pluripotency markers including Nanog, Oct4A, and Sox2 are upregulated in lung cancer cells, suggesting a direct effect on the cancer stem cells (CSCs) population [40]. More recent findings confirm a direct link for hCAP18/LL-37 acting on pancreatic CSCs to negatively affect tumor growth [30].…”

Section: Introductionmentioning

confidence: 59%

“…The expression level of hCAP-18/LL-37 is high in the tumor stroma of advanced primary and secondary pancreatic ductal adenocarcinomas (PDACs) [30]. The K-Ras +/LSL-G12D ; Trp53…”

Section: Pancreatic Cancermentioning

confidence: 99%

“…In prostate tumors, overexpressed mouse orthologue cathelicidin-related AMP (CRAMP) initially chemo-attracts immature myeloid progenitors (IMPs) to the tumor microenvironment (TME) and mediates differentiation and polarization of early myeloid progenitors into protumorigenic type 2 (M2) macrophages to help drive prostate cancer progression [62]. The stimulation of P2X 7 can promote migration of PC9 lung cells and T47D breast cancer cells [30], suggesting involvement of a similar P2X 7 -based mechanism in other solid tumors [63]. P2X 7 can trigger massive release of vascular endothelial growth factor (VEGF) from immune cells as well as tumor cells [31].…”

Section: Prostate Cancermentioning

confidence: 99%

“…Tumorigenesis can be dramatically inhibited by either reconstituting the KPC mice with bone marrow from cathelicidin-related antimicrobial peptide knockout mice or by pharmacologically inhibiting FPR2 and P2X 7 using the genetically engineered mouse model of pancreatic tumorigenesis [30].…”

Section: R172hmentioning

confidence: 99%

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Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Chen

Zou

et al. 2018

Cell Physiol Biochem

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LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. Mechanistically, LL-37-induced activation of membrane receptors and subsequent signaling pathways lead to alteration of cellular functions. Different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37. Meanwhile, the findings that vitamin D-dependent induction of cathelicidin in human macrophages activates the anti-cancer activity of tumor-associated macrophages (TAMs) and enhances antibody-dependent cellular cytotoxicity (ADCC) support critical roles of vitamin D-dependent induction of cathelicidin in cancer progression. This review describes novel advances involving the roles and mechanisms of human cathelicidin LL-37 in cancer.

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Section: Introductionmentioning

confidence: 59%

“…The expression level of hCAP-18/LL-37 is high in the tumor stroma of advanced primary and secondary pancreatic ductal adenocarcinomas (PDACs) [30]. The K-Ras +/LSL-G12D ; Trp53…”

Section: Pancreatic Cancermentioning

confidence: 99%

Section: Prostate Cancermentioning

confidence: 99%

Section: R172hmentioning

confidence: 99%

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Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Chen

Zou

et al. 2018

Cell Physiol Biochem

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“…Immune cells infiltrate solid tumors and serve either a tumor promoting-or tumor-suppressing role. Immune cells in the stroma such as tissue-associated macrophages (TAMs) secrete an immunomodulatory antimicrobial peptide 18/LL-37 (hCAP-18/LL-37; cathelicidin antimicrobial peptide) that increases the expression levels of the pluripotency associated genes, the rate of self-renewal and tumorigenicity via formyl peptide receptor 2 and P2X purinoceptor 7 receptor-dependent mechanisms (41). TAMs have also been demonstrated to secrete an enzyme termed cytidine deaminase, which degrades the bio-active form of gemcitabine in cancer cells and thereby renders the cells chemoresistant (42).…”

Section: Pancreatic Stellate Cells (Pscs)mentioning

confidence: 99%

Chemoresistance in pancreatic cancer: Emerging concepts

Gnanamony

Gondi

2017

Oncology Letters

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Abstract. Pancreatic cancer is one of the most lethal types of cancer in the world. The incidence of pancreatic cancer increases each year with no significant decrease in mortality. Pancreatic cancer is a complex disease, and this complexity is partly attributed to late diagnosis, an aggressive phenotype, environmental factors and lack of effective treatment options. Surgical resection followed by adjuvant chemotherapy is the treatment of choice for early stage cancer, whereas gemcitabine is the standard first line therapy for patients with advanced stage disease. Treatment regimens comprising folinic acid, 5-fluorouracil, irinotecan, oxaliplatin and nab-paclitaxel have demonstrated modest effects in improving median survival rates. A number of other chemotherapeutics are currently undergoing clinical trials as components of combination therapies with gemcitabine. An increasing number of novel molecular targets and cellular pathways are being identified, which highlights the complexity of this disease. The development of chemoresistance to gemcitabine is multifactorial and there exists an interplay between pancreatic cancer cells, the tumor microenvironment and cancer stem cells. These components appear to be governed by a complex network of non-coding RNAs such as micro RNAs and long non-coding RNAs. In the present study, studies describing previous research on the understanding of the factors associated with the development of chemoresistance to gemcitabine in pancreatic cancer are reviewed. A comprehensive understanding of the multiple pathways of chemoresistance is key to develop next generation therapeutics to pancreatic cancer.

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Macrophages in the pancreas: Villains by circumstances, not necessarily by actions

Cruz

Rohban

Esni

2020

Immunity Inflam & Disease

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Introduction Mounting evidence suggest that macrophages play crucial roles in disease and tissue regeneration. However, despite much efforts during the past decade, our knowledge about the extent of macrophages' contribution to adult pancreatic regeneration after injury or during pancreatic disease progression is still limited. Nevertheless, it is generally accepted that some macrophage features that normally would contribute to healing and regeneration may be detrimental in pancreatic cancer. Altogether, the current literature contains conflicting reports on whether macrophages act as friends or foe in these conditions. Methods and Results In this review, we briefly review the origins of tissue resident and infiltrating macrophages and the importance of cellular crosstalking between macrophages and other resident cells in tissue regeneration. The primary objective of this review is to summarize our knowledge of the distinct roles of tissue resident and infiltrating macrophages, the impact of M1 and M2 macrophage phenotypes, and emerging evidence on macrophage crosstalking in pancreatic injury, regeneration, and disease. Conclusion Macrophages are involved with various stages of pancreatic cancer development, pancreatitis, and diabetes. Elucidating their role in these conditions will aid the development of targeted therapeutic treatments.

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Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment

Cited by 121 publications

References 58 publications

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Chemoresistance in pancreatic cancer: Emerging concepts

Macrophages in the pancreas: Villains by circumstances, not necessarily by actions

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