Paneth cell–derived growth factors support tumorigenesis in the small intestine

Chen, Qing; Suzuki, Kohei; Sifuentes-Dominguez, Luis; Miyata, Naoteru; Song, Jie; Lopez, Adam M.; Starokadomskyy, Petro; Gopal, Purva; Dozmorov, Igor; Tan, Shuxin; Ge, Bujun; Burstein, Ezra

doi:10.26508/lsa.202000934

Cited by 6 publications

(6 citation statements)

References 45 publications

(55 reference statements)

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“…It has been reported that Paneth cell-specific deletion of Wnt3 leads to a reduction in small intestinal tumors but not colonic tumors in Apc Min/? mice [43]. We speculated that Wnt3 production might be reduced in the LAT1 fl/fl ; vilcre small intestine, and as expected, Wnt3 expression was substantially reduced at both the mRNA and protein levels (Fig.…”

Section: Organoids Derived From Lat1-deleted Tumors Displayed Fewer A...supporting

confidence: 58%

“…It would be acceptable to explain that the tumor number was not affected because the colon lacks Paneth cells; our data is further supported by a previous report, which showed Paneth cellspecific deletion of Wnt3 blocked Apc Min/? tumor formation in the small intestine but not in the colon [43]. Even so, LAT1 deficiency could have influenced tumor size.…”

Section: Discussionmentioning

confidence: 98%

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LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice

et al. 2023

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Background Amino acid transporters play an important role in supplying nutrition to cells and are associated with cell proliferation. L-type amino acid transporter 1 (LAT1) is highly expressed in many types of cancers and promotes tumor growth; however, how LAT1 affects tumor development is not fully understood. Methods To investigate the role of LAT1 in intestinal tumorigenesis, mice carrying LAT1 floxed alleles that also expressed Cre recombinase from the promoter of gene encoding Villin were crossed to an ApcMin/+ background (LAT1fl/fl; vil-cre; ApcMin/+), which were subject to analysis; organoids derived from those mice were also analyzed. Results This study showed that LAT1 was constitutively expressed in normal crypt base cells, and its conditional deletion in the intestinal epithelium resulted in fewer Paneth cells. LAT1 deletion reduced tumor size and number in the small intestine of ApcMin/+ mice. Organoids derived from LAT1-deleted ApcMin/+ intestinal crypts displayed fewer spherical organoids with reduced Wnt/β-catenin target gene expression, suggesting a low tumor-initiation capacity. Wnt3 expression was decreased in the absence of LAT1 in the intestinal epithelium, suggesting that loss of Paneth cells due to LAT1 deficiency reduced the risk of tumor initiation by decreasing Wnt3 production. Conclusions LAT1 affects intestinal tumor development in a cell-extrinsic manner through reduced Wnt3 expression in Paneth cells. Our findings may partly explain how nutrient availability can affect the risk of tumor development in the intestines.

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Section: Organoids Derived From Lat1-deleted Tumors Displayed Fewer A...supporting

confidence: 58%

Section: Discussionmentioning

confidence: 98%

LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice

et al. 2023

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“…Chen et al [ 109 ] showed cells of the Paneth cell lineage are present in intestinal adenomas. They secrete Wnt 3 and a deletion of Paneth cells leads to reduced growth of adenomas in the small intestine in APC min mice.…”

Section: Clinical Relevance Of Wnt Activation In the Intestinementioning

confidence: 99%

Intestinal Wnt in the transition from physiology to oncology

Swoboda¹,

Mittelsdorf²,

Chen³

et al. 2022

WJCO

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Adult stem cells are necessary for self-renewal tissues and regeneration after damage. Especially in the intestine, which self-renews every few days, they play a key role in tissue homeostasis. Therefore, complex regulatory mechanisms are needed to prevent hyperproliferation, which can lead in the worst case to carcinogenesis or under-activation of stem cells, which can result in dysfunctional epithelial. One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway. It is a highly conserved pathway, with β-catenin, a transcription factor, as target protein. Translocation of β-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripo-tency, proliferation, cell differentiation and regulation of cell death. This review presents a brief overview of the Wnt/β-catenin signaling pathway, the regulatory mechanism of this pathway and its role in intestinal homeostasis. Additionally, this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation. Furthermore, the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.

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“…Apart from being the source of stem cell signals in the small intestine, Paneth cells have previously been associated with β-catenin pathway activation in human adenomas [ 23 ] and a specific Paneth cell population expressing indoleamine-2,3-dioxygenase-1 was found to promote immune evasion in human colorectal cancer [ 24 ]. However, it remains controversial whether and how the presence of Paneth cells positively or negatively impact CRC malignancy [ 24 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Accumulation of Paneth Cells in Early Colorectal Adenomas Is Associated with Beta-Catenin Signaling and Poor Patient Prognosis

López-Arribillaga

Yan

Lobo-Jarne

et al. 2021

Cells

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Background: Previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal cancer remains unexplored. Methods: We performed histopathological evaluation and immunohistochemical analysis of early colorectal adenomas and carcinoma adenoma from patients at the Hospital del Mar in Barcelona. We then determined the possible correlation between the different parameters analyzed and with patient outcomes. Results: Paneth cells accumulate in a subset of human colorectal adenomas directly associated with Notch and Wnt/β-catenin activation. Adenoma areas containing Paneth cells display increased vessel density in the lamina propria and higher levels of the stem cell marker EphB2. In an in-house cohort of 200 colorectal adenoma samples, we also observed a significant correlation between the presence of Paneth cells and Wnt activation. Kaplan–Meier analysis indicated that early adenoma patients carrying Paneth cell-positive tumors display reduced disease-free survival compared with patients with Paneth cell-free lesions. Conclusions: Our results indicate that Paneth cells contribute to the initial steps of cancer progression by providing the stem cell niche to adenoma cells, which could be therapeutically exploited.

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Paneth cell–derived growth factors support tumorigenesis in the small intestine

Cited by 6 publications

References 45 publications

LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice

LAT1 expression influences Paneth cell number and tumor development in ApcMin/+ mice

Intestinal Wnt in the transition from physiology to oncology

Accumulation of Paneth Cells in Early Colorectal Adenomas Is Associated with Beta-Catenin Signaling and Poor Patient Prognosis

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