Ym1+ macrophages orchestrate fibrosis, lesion growth, and progression during development of murine pancreatic cancer

Martinez, Alicia K. Fleming; Döppler, Heike; Bastea, Ligia I.; Edenfield, Brandy; Liou, Geou-Yarh; Störz, Peter

doi:10.1016/j.isci.2022.104327

Cited by 10 publications

(22 citation statements)

References 63 publications

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“…Arg1 17 and Ym1 18 are fundamental features of M2 macrophages, with the secretion of Arg1 19 , Ym1 20 , MMP2 21 and MMP9 22 by macrophages promoting the metastasis of tumor cells. To study the secretion of Arg1, Ym1, MMP2 and MMP9 by M-M2 macrophages after downregulating CD206 expression, RT-qPCR and ELISA were used to assess their mRNA and protein levels, respectively.…”

Section: Resultsmentioning

confidence: 99%

CD206 modulates the role of M2 macrophages in the origin of metastatic tumors

Li,

Miao,

Suo

et al. 2024

J. Cancer

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Tumor metastasis is a key factor affecting the life of patients with malignant tumors. For the past hundred years, scientists have focused on how to kill cancer cells and inhibit their metastasis in vivo , but few breakthroughs have been made. Here we hypothesized a novel mode for cancer metastasis. We show that the phagocytosis of apoptotic tumor cells by macrophages leads to their polarization into the M2 phenotype, and that the expression of stem cell related as well as drug resistance related genes was induced. Therefore, it appears that M2 macrophages have "defected" and have been transformed into the initial "metastatic cancer cells", and thus are the source, at least in part, of the distal tissue tumor metastasis. This assumption is supported by the presence of fused cells with characteristics of both macrophage and tumor cell observed in the peripheral blood and ascites of patients with ovarian cancer. By eliminating the expression of CD206 in M2 macrophages using siRNA, we show that the growth and metastasis of tumors was suppressed using both in vitro cell line and with experimental in vivo mouse models. In summary, we show that M2 macrophages in the blood circulation underwent a "change of loyalty" to become "cancer cells" that transformed into distal tissue metastasis, which could be suppressed by the knockdown of CD206 expression.

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Section: Resultsmentioning

confidence: 99%

CD206 modulates the role of M2 macrophages in the origin of metastatic tumors

Li,

Miao,

Suo

et al. 2024

J. Cancer

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“…Dependent of their resistance to ROS, ADM cells can further progress to PanIN lesions, in which they may proliferate or show a senescent phenotype, or to DCLK1+ cells that can withstand high levels of intracellular ROS. At PanIN lesions and their surrounding microenvironment macrophages are mainly anti-inflammatory and drive lesion growth and fibrosis ( 10 , 18 , 24 ). But they also produce factors that induce ROS in neighboring acinar cells.…”

Section: Discussionmentioning

confidence: 99%

“…Other chemoattractants for macrophage are macrophage inflammatory protein-1 (MIP-1) and macrophage inflammatory protein-2 (MIP-2), produced by isolated PanIN lesion cells ( 22 ). Further, activated pancreatic stellate cells produce CXCL12 ( 24 ), which can act as a chemoattractant for a variety of immune cells, including macrophages. Moreover, the presence of C-C motif chemokine ligand 2 (CCL2), produced by a multitude of cells in the precancerous environment, attracts bone marrow-derived monocytes ( 23 ).…”

Section: Mutant Kras As An Inducer Of Macrophage Attractionmentioning

confidence: 99%

“…Once attracted to the ADM/PanIN lesion regions, several cells in their microenvironment produce macrophage proliferation factors. These include M-CSF, produced by activated pancreatic stellate cells ( 24 ) and by lesion cells ( 22 ).…”

Section: Mutant Kras As An Inducer Of Macrophage Attractionmentioning

confidence: 99%

“…Major producers of IL-13 are DCLK1+ lesion cells ( 19 ). Resulting M2 macrophages, best characterized in mice by expressing arginase ( Arg1 ), YM1 ( Chil3 ), Fizz1 , CD206 and Trem2 as markers ( 18 , 24 ), have multiple functions in the progression of lesions. They secrete factors such as TGFβ1 to activate pancreatic stellate cells (PSC) and establish the lesion microenvironment ( 24 ), and their ablation either chemically or via neutralization of IL-13 in KC mice leads to a drastic decrease in fibrosis ( 18 , 19 ).…”

Section: Alternatively Activated Macrophages and Roles In Lesion Prog...mentioning

confidence: 99%

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Macrophage-induced reactive oxygen species in the initiation of pancreatic cancer: a mini-review

Döppler,

Storz

2024

Front. Immunol.

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Pancreatic inflammation is a risk factor for the development of pancreatic cancer. Increased presence of inflammatory macrophages can be found in response to a KRAS mutation in acinar cells or in response to experimentally-induced pancreatitis. Inflammatory macrophages induce pancreatic acinar cells to undergo dedifferentiation to a duct-like progenitor stage, a process called acinar-to-ductal metaplasia (ADM). Occurrence of ADM lesions are believed to be the initiating event in tumorigenesis. Here we will discuss how macrophage-induced oxidative stress contributes to ADM and how ADM cells shape the fibrotic stroma needed for further progression.

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