Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers
<p>ALCAM transcript expression in tumours (<b>A</b>,<b>B</b>) and in relationship with peritoneal metastasis free survivals (<b>C</b>,<b>D</b>). (<b>A</b>,<b>B</b>): The ALCAM levels were compared between tumours from patients who remained disease-free and those who developed peritoneal metastases (<span class="html-italic">n</span> = 18 with peritoneal metastasis and <span class="html-italic">n</span> = 112 who were disease free for the gastric cancer group and <span class="html-italic">n</span> = 6 and <span class="html-italic">n</span> = 35 for the pancreatic cancer group). * <span class="html-italic">p</span> = 0.037, ** <span class="html-italic">p</span> = 0.01. (<b>C</b>,<b>D</b>): Gastric cancer patients with high levels of ALCAM had a significantly shorter survival than those with low levels (<span class="html-italic">p</span> = 0.006). A similar shorter survival with seen with pancreatic cancer patients although this is yet to reach statistical significance (<span class="html-italic">p</span> = 0.208).</p> "> Figure 2
<p>Creation of cell models with differential expression of ALCAM as confirmed by PCR (<b>left panel</b>) and quantitative PCR (<b>right panel</b>). (<b>A</b>): The ALCAM transcript expression in MET5A control (MET5A<sup>Control</sup>) and ALCAM knockdown cells (MET5A<sup>ALCAM-KD</sup>). (<b>B</b>): The ALCAM transcript expression levels in HGC-27 control (HGC27<sup>Control</sup>) and ALCAM knockdown cells (HGC27<sup>ALCAM-KD</sup>) (<b>left</b>), as well as AGS control (AGS <sup>Control</sup>) and ALCAM knockdown cells (AGS<sup>ALCAM-KD</sup>) (<b>right</b>). (<b>C</b>): The ALCAM transcript expression levels in PANC-1 Control (PANC1<sup>Control</sup>) and ALCAM knockdown cells (PANC1<sup>ALCAM-KD</sup>) (<b>left</b>), as well as MIA PaCa-2 Control (MIA<sup>Control</sup>) and ALCAM overexpression cells (MIA<sup>ALCAM-OE</sup>) (<b>right</b>). *: ALCAM-modified cell lines which showed significant changes compared with their respective control cells (<span class="html-italic">p</span> < 0.05). (<b>D</b>): Knockdown of ALCAM protein in the respective cell lines as shown by protein blotting.</p> "> Figure 3
<p>ECIS based evaluation of gastric adhesion to mesothelial cells. (<b>A</b>–<b>D</b>): Adhesion of HGC27 cells to MET5A mesothelial cells; (<b>E</b>–<b>H</b>): Adhesion of AGS cells to MET5A cells; Shown are monitoring at 4000 Hz. MET5A<sup>Control</sup>, AGS<sup>Control</sup>, HGC27<sup>Control</sup>: control transfected cells; MET5A<sup>ALCAM-KD</sup>, AGS<sup>ALCAM-KD</sup>, HGC27<sup>ALCAM-KD</sup>: cells with ALCAM knockdown by way of cell transfection. Replicate <span class="html-italic">n</span> = 4.</p> "> Figure 4
<p>Interaction between HGC-27 (<b>left</b>) or AGS (<b>right</b>) gastric cancer cells and MET5A mesothelial cells. Both gastric cancer cell lines after knocking down ALCAM showed reduced adhesion to MET5A mesothelial cells. * Groups of cells with ALCAM knockdown compared with the groups of control MET5A cells plus control cancer cells (<span class="html-italic">p</span> < 0.05, replicate <span class="html-italic">n</span> = 4).</p> "> Figure 5
<p>ECIS based evaluation of pancreatic adhesion to mesothelial cells. (<b>A</b>–<b>D</b>): Adhesion of PANC1 cells to MET5A mesothelial cells; (<b>E</b>–<b>H</b>): Adhesion of MIA PaCa-2 cells to MET5A cells. Shown are monitoring at 4000Hz. MET5A<sup>Control</sup>, PANC1<sup>Control</sup>, MIAPaCa2<sup>Control</sup>: control transfected cells; MET5A<sup>ALCAM-KD</sup>, PANC1<sup>ALCAM-KD</sup>: cells with ALCAM knockdown by way of cell transfection; MIAPaCa2<sup>ALCAM-OE</sup>: cells with ALCAM overexpression by way of cell transfection. Replicate <span class="html-italic">n</span> = 4.</p> "> Figure 6
<p>Interaction between PANC-1 (<b>left</b>) and MIA PaCa-2 (<b>right</b>) pancreatic cancer cells and MET5A mesothelial cells. Left: PANC-1 cells after knocking down ALCAM by way of knocking down showed reduced adhesion to MET5A mesothelial cells. Right: Overexpression of ALCAM in MIA PaCa-2 cells had augmented the interaction with mesothelial cells. * Groups of cells with ALCAM modification compared with groups of control MET5A cells plus control cancer cells (<span class="html-italic">p</span> < 0.05, replicate <span class="html-italic">n</span> = 4).</p> "> Figure 7
<p>Interaction between pancreatic cancer cell line PANC-1 and mesothelial cell line MET5A as determined by the DiI based assays. (<b>Top</b>): Representative images (×10 magnification) of pancreatic cancer cells (PANC-1 Control and ALCAM knockdown cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). (<b>A</b>–<b>D</b>) represent wells without any treatment and E-H represent wells treated with 2 µg/mL sALCAM. (<b>A</b>,<b>E</b>): MET5A Control + PANC-1 Control; (<b>B</b>,<b>F</b>): MET5A Control + PANC-1 ALCAM knockdown; (<b>C</b>,<b>G</b>): MET5A ALCAM knockdown + PANC-1 Control; (<b>D</b>,<b>H</b>): MET5A ALCAM knockdown + PANC-1 ALCAM knockdown. (<b>Bottom</b>): Graphical representation of pancreatic cancer cells (PANC-1 Control and ALCAM knockdown cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). * Groups which showed significantly differences compared with “MET5A Control + PANC-1 Control” group (<span class="html-italic">p</span> < 0.05).</p> "> Figure 8
<p>Interaction between pancreatic cancer cell line MIA PaCa-2 and mesothelial cell line MET5A as determined by the DiI based assays. (<b>Top</b>): Representative images (×10 magnification) of pancreatic cancer cells (MIA PaCa-2 Control and ALCAM overexpression cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). (<b>A</b>–<b>D</b>) represent wells without any treatment and E-H represent wells treated with 2 µg/mL sALCAM. (<b>A</b>,<b>E</b>): MET5A control + MIA PaCa-2 control; (<b>B</b>,<b>F</b>): MET5A control + MIA PaCa-2 overexpression; (<b>C</b>,<b>G</b>): MET5A knockdown + MIA PaCa-2 control; (<b>D</b>,<b>H</b>): MET5A knockdown + MIA PaCa-2 overexpression. (<b>Bottom</b>): Graphical representation of pancreatic cancer cells (MIA Control and ALCAM overexpression cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). *: Groups which showed significantly differences compared with “MET5A Control + MIA Control” group (<span class="html-italic">p</span> < 0.05); #: Groups which showed significantly differences compared with “MET5A ALCAM-KD + MIA Control” group (<span class="html-italic">p</span> < 0.05); &: Groups which showed significantly differences compared with” MET5A Control+ MIA Control + sALCAM” group (<span class="html-italic">p</span> < 0.05); @: Groups which showed significantly differences compared with “MET5A Control + MIA ALCAM-OE” group (<span class="html-italic">p</span> < 0.05); <span>$</span>: Groups which showed significantly differences compared with “MET5A ALCAM-KD + MIA ALCAM-OE” (<span class="html-italic">p</span> < 0.05).</p> "> Figure 9
<p>Interaction between gastric cancer cell line HGC-27 and mesothelial cell line MET5A as determined by the DiI based assays. (<b>Top</b>): Representative images (×10 magnification) of gastric cancer cells (HGC-27 Control and ALCAM knockdown cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). (<b>A</b>–<b>D</b>) represent wells without any treatment and E-H represent wells treated with 2 µg/mL sALCAM. (<b>A</b>,<b>E</b>): MET5A Control + HGC27 Control; (<b>B</b>,<b>F</b>): MET5A Control + HGC27 ALCAM knockdown; (<b>C</b>,<b>G</b>): MET5A ALCAM knockdown + HGC27 Control; (<b>D</b>,<b>H</b>): MET5A ALCAM knockdown + HGC27 ALCAM knockdown. (<b>Bottom</b>): Graphical representation of gastric cancer cells (HGC-27 Control and ALCAM knockdown cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). *: Groups which showed significantly differences compared with “MET5A Control + HGC27 Control” group (<span class="html-italic">p</span> < 0.05). #: Groups which showed significantly differences compared with “MET5A Control + HGC27 Control + sALCAM” group (<span class="html-italic">p</span> < 0.05); &: Groups which showed significantly differences compared with” MET5A Control+ HGC27 ALCAM-KD” group (<span class="html-italic">p</span> < 0.05); <span>$</span>: Groups which showed significantly differences compared with “MET5A ALCAM-KD + HGC27 ALCAM-KD” group (<span class="html-italic">p</span> < 0.05).</p> "> Figure 10
<p>Interaction between gastric cancer cell line AGS and mesothelial cell line MET5A as determined by the DiI based assays. (<b>Top</b>): Representative images (×10 magnification) of gastric cancer cells (AGS Control and ALCAM knockdown cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). (<b>A</b>–<b>D</b>) represent wells without any treatment and E-H represent wells treated with 2 µg/mL sALCAM. (<b>A</b>,<b>E</b>): MET5A control + AGS control; (<b>B</b>,<b>F</b>): MET5A control + AGS ALCAM knockdown; (<b>C</b>,<b>G</b>): MET5A ALCAM knockdown + AGS Control; (<b>D</b>,<b>H</b>): MET5A ALCAM knockdown + AGS ALCAM knockdown. (<b>Bottom</b>): Graphical representation of pancreatic cancer cells (AGS Control and ALCAM knockdown cells) adherence to mesothelial cells (MET5A Control and ALCAM knockdown cells). *: Groups which showed significantly differences compared with “MET5A Control + AGS Control” group (<span class="html-italic">p</span> < 0.05). #: Groups which showed significantly differences compared with “MET5A Control + AGS ALCAM-KD” group (<span class="html-italic">p</span> < 0.05); &: Groups which showed significantly differences compared with” MET5A Control + AGS Control + sALCAM” group (<span class="html-italic">p</span> < 0.05).</p> "> Figure 11
<p>Tumour-mesothelial interaction and the role of SRC kinase. (<b>A</b>). The effects of SRC inhibitor (SRCi), AZM475271 on the interaction between pancreatic cancer cell MIA PaCa-2 and mesothelial cells by DiI assay. The SRC inhibitor suppressed the adhesion between 80 nM to 10 μM, to a degree similar to that of soluble ALCAM (* <span class="html-italic">p</span> < 0.05 versus control). (<b>B</b>). Representative images of tumour-mesothelial interaction. (<b>C</b>). Expression of potential ALCAM interacting partners in gastric and pancreatic cancer and mesothelial cells. All cells were negative for CD6 and L1CAM except that AGS was weakly positive for L1CAM (CD171). Cells were otherwise positive for SRC, and the ERM family ezrin and moesin. (<b>D</b>). SRC kinase expression and phosphorylation. MET5A cells were treated with soluble ALCAM (sALCAM) at 2.5 μg/mL or the SRC inhibitor (SRCi) AZM475271 at 400 nM for 40 min. Total SRC and phosphorylated-SRC (pSRC) was detected by protein blotting. Both sALCAM and SRCi inhibited the phosphorylation of SRC as shown in the bar graph. Insert: band density of respective SRC and p-SRC.</p> "> Figure 12
<p>The proposed mechanism of ALCAM mediated tumour-endothelial interactions. Following shedding of cancer cells from the primary site, stomach or pancreas (<b>A</b>), the metastatic cancer cells (seeds) in the abdominal cavity come to contact the peritoneal mesothelial cells (‘soil’) (<b>B</b>), all expressed high levels of ALCAM but neither expressed CD6 or L1CAM (<b>C</b>), which initiates the ALACAM-ALCAM homotypic interaction. Supported by the machinery including the subcoat protein ERM and signalling kinase SRC, ALCAM mediates the tumour-mesothelial interaction. Soluble ALCAM as an extracellular antagonist or small compound inhibitory molecule to SRC kinase as intracellular inhibitor, can disrupt this ALCAM-ALCAM mediated tumour-endothelial interaction (<b>D</b>) and offer a potential therapeutic opportunity.</p> ">
Abstract
:1. Introduction
2. Results
2.1. ALCAM in Tumours Which Developed Peritoneal Metastasis
2.2. The Creation of Cell Models with Altered Levels of ALCAM
2.3. Dynamic Monitoring of Gastric Tumour-Mesothelial Interaction Assocaited with ALCAM Level Alteration
2.4. Dynamic Monitoring of Pancreatic Tumour-Mesothelial Interactions Associated with ALCAM Alterations
2.5. DiI Based Pancreatic Tumour-Mesothelial Cell Interactions
2.6. DiI Based Gastric Tumour-Mesothelial Cell Interactions
2.7. The Interaction of Tumour-Mesothelial Cells Was Primarily Due to the Action of ALCAM and Mediated by the SRC Pathway
3. Discussion
4. Conclusions
5. Materials and Methods
5.1. Cell Lines and Cell Cultures
5.2. Key Reagents
5.3. Generation of ALCAM Modified Cells
5.4. Clinical Cohorts
5.5. Determination of ALCAM in Tissues
5.6. Tumour-Mesothelial Interaction Assay
5.7. Dynamic Monitoring of Tumour-Mesothelial Interactions
5.8. Protein Preparation and Protein Electrophesis
5.9. Statistical Methods
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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HR | P * | Survival Time | |
---|---|---|---|
Gastric cancer | 8.79 | 0.003 | 92.8 ± 2.3 vs. 80.2 ± 4.5 Months |
Pancreatic cancer | 2.84 | 0.208 | 93.1 ± 11.3 vs. 66.5 ± 15.3 Months |
Target | Forward Primer | Reverse Primer * |
---|---|---|
ALCAM | ttatcataccttgccgatt | gggtggaagtcatggtatag |
ALCAM | caggaggttgaaggactaaa | actgaacctgaccgtacagggatcagttttctttgtca |
CD6 | ctactgcggccacaaag | actgaacctgaccgtacactcggaagtgtacctcca |
L1CAM | ccacttgtttaaggagagga | actgaacctgaccgtacagatgatggcactcacaaag |
SRC | tgtggccctctatgactatg | aaactccccttgctcatgta |
Ezrin | tggagagagagaaagagcag | ttcttctctgcctcagtgat |
Moesin | taagaaggctcagcaagaac | cttcttggactcatctctgg |
GAPDH | ggctgcttttaactctggta | gactgtggtcatgagtcctt |
GAPDH | aaggtcatccatgacaactt | actgaacctgaccgtacagccatccacagtcttctg |
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Yang, Y.M.; Ye, L.; Ruge, F.; Fang, Z.; Ji, K.; Sanders, A.J.; Jia, S.; Hao, C.; Dou, Q.P.; Ji, J.; et al. Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers. Int. J. Mol. Sci. 2023, 24, 876. https://doi.org/10.3390/ijms24010876
Yang YM, Ye L, Ruge F, Fang Z, Ji K, Sanders AJ, Jia S, Hao C, Dou QP, Ji J, et al. Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers. International Journal of Molecular Sciences. 2023; 24(1):876. https://doi.org/10.3390/ijms24010876
Chicago/Turabian StyleYang, Yi Ming, Lin Ye, Fiona Ruge, Ziqian Fang, Ke Ji, Andrew J. Sanders, Shuqin Jia, Chunyi Hao, Q. Ping Dou, Jiafu Ji, and et al. 2023. "Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers" International Journal of Molecular Sciences 24, no. 1: 876. https://doi.org/10.3390/ijms24010876