Immunohistochemical analysis of L1 cell adhesion molecule and high endothelial venules in breast cancer brain metastasis

Karpathiou, Georgia; Camy, Florian; Dumollard, Jean Marc; Péoc’h, Michel

doi:10.1016/j.prp.2021.153484

Cited by 8 publications

(9 citation statements)

References 20 publications

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“…Here, we elucidated the underlying mechanism of vessel co-option from the "hijackee" and Vessel co-option is a complex process involving multiple cell types, such as tumor cells, endothelial cells, pericytes, and immune cells. The key regulatory roles of tumor cells in vessel co-option have also been widely demonstrated by previous studies (13)(14)(15)(16). Tumor cells hijacking blood vessels can induce expression of angiopoietin 2 and VEGF in vascular endothelial cells, which subsequently results in regression of the blood vessels (43).…”

Section: Discussionmentioning

confidence: 67%

“…Although vessel co-option has been known for more than 20 years (41), effective strategies to inhibit or disrupt vessel co-option are still lacking. Alternatively, genetic depletion of L1CAM, Serpin B1, ARP2/3, RUNX1, or ITGA5 in tumor cells has been demonstrated to attenuate vessel co-option (13)(14)(15)(16). Angiogenesis inhibitors are ineffective on mature vessels with high pericyte coverage, which is mainly due to the pro-survival effect of pericytes on endothelial cells (60).…”

Section: The Intercellular Crosstalk Between Liver Sinusoidal Endothe...mentioning

confidence: 99%

“…Currently, a few studies are primarily focused on the "hijacker"-tumor cells in vessel co-option (12). For instance, overexpression of neuronal cell adhesion molecule L1 (L1CAM), Serpin B1, actinrelated protein 2/3 complex (ARP2/3), runt related transcription factor-1 (RUNX1), and integrin α5β1 (ITGA5) in tumor cells facilitate vessel co-option by promoting the epithelial-mesenchymal transition (EMT) and motility of tumor cells (13)(14)(15)(16)).…”

Section: Introductionmentioning

confidence: 99%

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Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models

Qi¹,

Fan²,

Huang³

et al. 2022

Journal of Clinical Investigation

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Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to anti-angiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on the "hijacker" tumor cells, whereas the function of the "hijackee" sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant CRCLM xenografts was associated with increased expression of fibroblast activation protein alpha (FAPα) in the co-opted hepatic stellate cells (HSCs), which was dramatically attenuated in HSC-specific conditional Fap-knockout mice bearing CRCLM allografts.Mechanistically, bevacizumab treatment induced hypoxia to upregulate the expression of fibroblast growth factor-binding protein 1 (FGFBP1) in tumor cells. Gain-or lossof-function experiments revealed that the bevacizumab-resistant tumor cell-derived FGFBP1 induced FAPα expression by enhancing the paracrine FGF2-FGFR1-ERK1/2-EGR1 signaling pathway in HSCs. FAPα promoted CXCL5 secretion in HSCs, which activated CXCR2 to promote the epithelial-mesenchymal transition of tumor cells and the recruitment of myeloid-derived suppressor cells. These findings were further validated in CRCLM patient-derived tumor tissues. Targeting FAPα + HSCs effectively disrupted the co-opted sinusoidal blood vessels and overcame bevacizumab resistance.Our study highlights the role of FAPα + HSCs in vessel co-option and provides an effective strategy to overcome the vessel co-option-mediated bevacizumab resistance.

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Section: Discussionmentioning

confidence: 67%

Section: The Intercellular Crosstalk Between Liver Sinusoidal Endothe...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models

Qi¹,

Fan²,

Huang³

et al. 2022

Journal of Clinical Investigation

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“…However, a recent IHC study failed to observe L1CAM expression in an entire set of thirty resected breast cancer brain metastases by IHC [24]. One possible explanation the authors gave is that, after developing macro-metastases in the brain, L1CAM is no longer necessary, and then downregulated [24]. Herein, we offered a possibility that L1CAM downregulation could be due to FOXC1 silencing.…”

Section: Discussionmentioning

confidence: 75%

“…It is known that FOXC1 boosts distant metastasis in TNBC to both lung and brain [12,13,22], and L1CAM may be the key molecular in vascular co-option in brain metastasis [17,23]. However, a recent IHC study failed to observe L1CAM expression in an entire set of thirty resected breast cancer brain metastases by IHC [24]. One possible explanation the authors gave is that, after developing macro-metastases in the brain, L1CAM is no longer necessary, and then downregulated [24].…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of forkhead box C1 and L1 cell adhesion molecule contributes to triple-negative breast cancer progression

Zhang

Lin

et al. 2023

Preprint

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Purpose Forkhead box C1 (FOXC1) may act as a therapeutic target for triple-negative breast cancer (TNBC) but without a comprehensive understanding of its regulations, especially at the upstream. L1 cell adhesion molecule (L1CAM) is a transmembrane glycoprotein that may involve in brain metastasis. Indicated by a positive correlation between FOXC1 and L1CAM transcripts, this study aims to further examine their relation in the process of TNBC.Methods FOXC1 and L1CAM transcripts were downloaded from two public datasets, and their proteins were examined in four TNBC cell lines. FOXC1 and L1CAM were separately knocked down in BT549 cells; L1CAM was overexpressed in BT549-shFOXC1, MDA-MB-231, and HCC1937 cells. CCK-8, transwell and wound healing assays were conducted in these cells, so was immunohistochemical staining in tumors.Results L1CAM and FOXC1 transcripts were positively correlated in public datasets. BT549-shFOXC1 cells showed a decreased L1CAM expression both at the transcriptional and protein levels. Intriguingly, BT549-siL1CAM cells displayed decreased FOXC1 proteins, but exerted little effect on FOXC1 transcripts. Conversely, overexpression of L1CAM resulted in upregulation of FOXC1 protein without substantial change in FOXC1 mRNA, that consistently observed in BT549-shFOXC1, MDA-MB-231-L1CAM and HCC1937-L1CAM cells. Additionally, decreased or increased capacities of cell proliferation, migration, and invasion were seen along with down- or up-regulation of FOXC1 or L1CAM. Finally, a positive correlation between L1CAM and FOXC1 proteins was observed in human TNBC tumors.Conclusion FOXC1 and L1CAM display coregulation at the protein level but not mRNA level to positively affect cell proliferation, migration and invasion in TNBC.

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DH5α Outer Membrane‐Coated Biomimetic Nanocapsules Deliver Drugs to Brain Metastases but not Normal Brain Cells via Targeting GRP94

Zhou

Chen

Zeng

et al. 2023

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Receptor‐mediated vesicular transport has been extensively developed to penetrate the blood‐brain barrier (BBB) and has emerged as a class of powerful brain‐targeting delivery technologies. However, commonly used BBB receptors such as transferrin receptor and low‐density lipoprotein receptor‐related protein 1, are also expressed in normal brain parenchymal cells and can cause drug distribution in normal brain tissues and subsequent neuroinflammation and cognitive impairment. Here, the endoplasmic reticulum residing protein GRP94 is found upregulated and relocated to the cell membrane of both BBB endothelial cells and brain metastatic breast cancer cells (BMBCCs) by preclinical and clinical investigations. Inspired by that Escherichia coli penetrates the BBB via the binding of its outer membrane proteins with GRP94, avirulent DH5α outer membrane protein‐coated nanocapsules (Omp@NCs) are developed to cross the BBB, avert normal brain cells, and target BMBCCs via recognizing GRP94. Embelin (EMB)‐loaded Omp@EMB specifically reduce neuroserpin in BMBCCs, which inhibits vascular cooption growth and induces apoptosis of BMBCCs by restoring plasmin. Omp@EMB plus anti‐angiogenic therapy prolongs the survival of mice with brain metastases. This platform holds the translational potential to maximize therapeutic effects on GRP94‐positive brain diseases.

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Immunohistochemical analysis of L1 cell adhesion molecule and high endothelial venules in breast cancer brain metastasis

Cited by 8 publications

References 20 publications

Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models

Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models

Reciprocal regulation of forkhead box C1 and L1 cell adhesion molecule contributes to triple-negative breast cancer progression

DH5α Outer Membrane‐Coated Biomimetic Nanocapsules Deliver Drugs to Brain Metastases but not Normal Brain Cells via Targeting GRP94

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