Impact of the Microenvironment on Tumour Budding in Colorectal Cancer

Georges, Laurent M. C.; Verset, Laurine; Zlobec, Inti; Demetter, Pieter; Wever, Olivier De

doi:10.1007/978-3-030-02771-1_7

Cited by 6 publications

(5 citation statements)

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“…Tumor budding is defined as the presence of disseminated single CRC cells or small clusters of up to five CRC cells, which are often found in the TME with infiltrative growth patterns. CRC tumor budding is commonly associated with invasive tumor growth, epithelial–mesenchymal transition (EMT), and lymphovascular invasion (Georges et al , ; Koelzer et al , ). CRC tissue characterized by higher TRPM4 staining intensity was associated with significantly more tumor buds in the TME (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of tumor features from 379 patients revealed that high levels of TRPM4 protein were related to aggressive tumor features, including high numbers of tumor buds—which is a sign of EMT, metastasis, and more aggressive infiltrative growth patterns in CRC (Fig. ) (Georges et al , ; Karamitopoulou et al , ; Koelzer et al , ). TRPM4 contributes to migration in multiple cellular systems, including immune cells, vascular endothelial cells, and PCa cells (Barbet et al , ; Holzmann et al , ; Sagredo et al , ; Sarmiento et al , ; Shimizu et al , ).…”

Section: Discussionmentioning

confidence: 99%

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TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells

et al. 2019

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells

et al. 2019

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“…This observation is in line with those observed in other cancers pertaining to TRPM4 and EMT as follows: (1) Independent studies have shown that TRPM4 knockdown could suppress migration and invasion of prostate cancer cells through reduction of EMT. Knockdown of TRPM4 correlated with reduction of mesenchymal markers including N-cadherin and vimentin, while expression of epithelial markers was increased such as E-cadherin and Snail [20,21]; (2) In colorectal cancer, tumor budding is characterized by presence of disseminated colorectal cancer cells driven by EMT for metastasis [52][53][54]. High TRPM4 protein intensity was associated with increased number of tumor buds and infiltrative growth pattern in colorectal cancer patient cases, and late-stage metastatic colorectal cancer cell lines had higher TRPM4 protein expression [24]; (3) TRPM4 transcript expression was positively associated with EMT genes of adhesion molecules or extracellular matrix origin including collagens (e.g.…”

Section: Discussionmentioning

confidence: 99%

TRPM4 is overexpressed in breast cancer associated with estrogen response and epithelial-mesenchymal transition gene sets

Wong

Hussain

2020

PLoS ONE

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Ion channels form an important class of drug targets in malignancies. Transient receptor potential cation channel subfamily M member 4 (TRPM4) plays oncological roles in various solid tumors. Herein, we examined TRPM4 protein expression profile by immunohistochemistry (IHC) in breast cancer cases compared with normal breast ducts, its association with clinico-demographical parameters, and its potential function in breast cancers by Gene Set Enrichment Analysis (GSEA). Data-mining demonstrated that TRPM4 transcript levels were significantly higher in The Cancer Genome Atlas series of breast cancer cases (n = 1,085) compared with normal breast tissues (n = 112) (p = 1.03 x 10 −11 ). Our IHC findings in tissue microarrays showed that TRPM4 protein was overexpressed in breast cancers (n = 83/99 TRPM4 + ; 83.8%) compared with normal breast ducts (n = 5/10 TRPM4 + ; 50%) (p = 0.022). Higher TRPM4 expression (median frequency cut-off) was significantly associated with higher lymph node status (N1-N2 vs N0; p = 0.024) and higher stage (IIb-IIIb vs I-IIa; p = 0.005). GSEA evaluation in three independent gene expression profiling (GEP) datasets of breast cancer cases (GSE54002, n = 417; GSE20685, n = 327; GSE23720, n = 197) demonstrated significant association of TRPM4 transcript expression with estrogen response and epithelial-mesenchymal transition (EMT) gene sets (p<0.01 and false discovery rate<0.05). These gene sets were not enriched in GEP datasets of normal breast epithelium cases (GSE10797, n = 5; GSE9574, n = 15; GSE20437, n = 18). In conclusion, TRPM4 protein expression is upregulated in breast cancers associated with worse clinico-demographical parameters, and TRPM4 potentially regulates estrogen receptor signaling and EMT progression in breast cancer.

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“…TRPM4 protein was reported to be highly expressed in tumor buds, and high expression of TRPM4 was correlated with a higher number of tumor buds and an increased percentage of the infiltrative tumor border configuration. These small clusters of up to five cancer cells, called tumor buds, and an infiltrative tumor border configuration were correlated with lymphatic vessel invasion and lymph node metastasis in CRC [113][114][115], thereby linking TRPM4 expression to worse patient outcomes. The discrepancy between these three studies could be due to the type of samples or different sample sizes that were analyzed.…”

Section: Trpm4 Expression In Cancermentioning

confidence: 99%

TRPM4 in Cancer—A New Potential Drug Target

2021

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Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

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Impact of the Microenvironment on Tumour Budding in Colorectal Cancer

Cited by 6 publications

References 58 publications

TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells

TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells

TRPM4 is overexpressed in breast cancer associated with estrogen response and epithelial-mesenchymal transition gene sets

TRPM4 in Cancer—A New Potential Drug Target

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