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Divergent roles of CD44 and carcinoembryonic antigen in colon cancer metastasis.

ABSTRACT: After separating from a primary tumor, metastasizing cells enter the circulatory system and interact with host cells before lodging in secondary organs. Previous studies have implicated the surface glycoproteins CD44 and carcinoembryonic antigen (CEA) in adhesion, migration, and invasion, suggesting that they may influence metastatic progression. To elucidate the role of these multifunctional molecules while avoiding the potential drawbacks of ectopic expression or monoclonal antibody treatments, we silenced the expression of CD44 and/or CEA in LS174T colon carcinoma cells and analyzed their ability to metastasize in 2 independent mouse models. Quantitative PCR revealed that CD44 knockdown increased lung and liver metastasis >10-fold, while metastasis was decreased by >50% following CEA knockdown. These findings were corroborated by in vitro experiments assessing the metastatic potential of LS174T cells. Cell migration was decreased as a result of silencing CEA but was enhanced in CD44-knockdown cells. In addition, CD44 silencing promoted homotypic aggregation of LS147T cells, a phenotype that was reversed by additional CEA knockdown. Finally, CD44-knockdown cells exhibited greater mechanical compliance than control cells, a property that correlates with increased metastatic potential. Collectively, these data indicate that CEA, but not CD44, is a viable target for therapeutics aimed at curbing colon carcinoma metastasis.

SUBMITTER: Dallas MR

PROVIDER: S-EPMC3360151 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Divergent roles of CD44 and carcinoembryonic antigen in colon cancer metastasis.

Dallas Matthew R MR Liu Guosheng G Chen Wei-Chiang WC Thomas Susan N SN Wirtz Denis D Huso David L DL Konstantopoulos Konstantinos K

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20120313 6

After separating from a primary tumor, metastasizing cells enter the circulatory system and interact with host cells before lodging in secondary organs. Previous studies have implicated the surface glycoproteins CD44 and carcinoembryonic antigen (CEA) in adhesion, migration, and invasion, suggesting that they may influence metastatic progression. To elucidate the role of these multifunctional molecules while avoiding the potential drawbacks of ectopic expression or monoclonal antibody treatments ...[more]

PMID: 22415308

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Project description:ImportanceGuidelines recommend measuring preoperative carcinoembryonic antigen (CEA) in patients with colon cancer. Although persistently elevated CEA after surgery has been associated with increased risk for metastatic disease, prognostic significance of elevated preoperative CEA that normalized after resection is unknown.ObjectiveTo investigate whether patients with elevated preoperative CEA that normalizes after colon cancer resection have a higher risk of recurrence than patients with normal preoperative CEA.Design, setting, and participantsThis retrospective cohort analysis was conducted at a comprehensive cancer center. Consecutive patients with colon cancer who underwent curative resection for stage I to III colon adenocarcinoma at the center from January 2007 to December 2014 were identified.ExposuresPatients were grouped into 3 cohorts: normal preoperative CEA, elevated preoperative but normalized postoperative CEA, and elevated preoperative and postoperative CEA.Main outcomes and measuresThree-year recurrence-free survival (RFS) and hazard function curves over time were analyzed.ResultsA total of 1027 patients (461 [50.4%] male; median [IQR] age, 64 [53-75] years) were identified. Patients with normal preoperative CEA had 7.4% higher 3-year RFS (n = 715 [89.7%]) than the combined cohorts with elevated preoperative CEA (n = 312 [82.3%]) (P = .01) but had RFS similar to that of patients with normalized postoperative CEA (n = 142 [87.9%]) (P = .86). Patients with elevated postoperative CEA had 14.9% lower RFS (n = 57 [74.5%]) than the combined cohorts with normal postoperative CEA (n = 857 [89.4%]) (P = .001). The hazard function of recurrence for elevated postoperative CEA peaked earlier than for the other cohorts. Multivariate analyses confirmed that elevated postoperative CEA (hazard ratio [HR], 2.0; 95% CI, 1.1-3.5), but not normalized postoperative CEA (HR, 0.77; 95% CI, 0.45-1.30), was independently associated with shorter RFS.Conclusions and relevanceElevated preoperative CEA that normalizes after resection is not an indicator of poor prognosis. Routine measurement of postoperative, rather than preoperative, CEA is warranted. Patients with elevated postoperative CEA are at increased risk for recurrence, especially within the first 12 months after surgery.

Project description:Pretargeted radioimmunotherapy (PRIT) with the β-emitting radionuclide 177Lu is an attractive approach to treat carcinoembryonic antigen (CEA)-expressing tumors. The therapeutic efficacy of PRIT might be improved using α-emitting radionuclides such as 213Bi. Herein, we report and compare the tumor-targeting properties and therapeutic efficacy of 213Bi and 177Lu for PRIT of CEA-expressing xenografts, using the bispecific monoclonal antibody TF2 (anti-CEA × anti-histamine-succinyl-glycine [HSG]) and the di-HSG-DOTA peptide IMP288. Methods: The in vitro binding characteristics of 213Bi-IMP288 were compared with those of 177Lu-IMP288. Tumor targeting of 213Bi-IMP288 and 177Lu-IMP288 was studied in mice bearing subcutaneous LS174T tumors that were pretargeted with TF2. Finally, the effect of 213Bi-IMP288 (6, 12, or 17 MBq) and 177Lu-IMP288 (60 MBq) on tumor growth and survival was assessed. Toxicity was determined by monitoring body weight, analyzing blood samples for hematologic and renal toxicity (hemoglobin, leukocytes, platelets, creatinine), and immunohistochemical analysis of the kidneys. Results: The in vitro binding characteristics of 213Bi-IMP288 (dissociation constant, 0.45 ± 0.20 nM) to TF2-pretargeted LS174T cells were similar to those of 177Lu-IMP288 (dissociation constant, 0.53 ± 0.12 nM). In vivo accumulation of 213Bi-IMP288 in LS174T tumors was observed as early as 15 min after injection (9.2 ± 2.0 percentage injected dose [%ID]/g). 213Bi-IMP288 cleared rapidly from the circulation; at 30 min after injection, the blood levels were 0.44 ± 0.28 %ID/g. Uptake in normal tissues was low, except for the kidneys, where uptake was 1.8 ± 1.1 %ID/g at 30 min after injection. The biodistribution of 213Bi-IMP288 was comparable to that of 177Lu-IMP288. Mice treated with a single dose of 213Bi-IMP288 or 177Lu-IMP288 showed significant inhibition of tumor growth. Median survival for the groups treated with phosphate-buffered saline, 6 MBq 213Bi-IMP288, 12 MBq 213Bi-IMP288, and 60 MBq 177Lu-IMP288 was 22, 31, 45, and 42 d, respectively. Mice receiving 17 MBq 213Bi-IMP288 showed significant weight loss, resulting in a median survival of only 24 d. No changes in hemoglobin, platelets, or leukocytes were observed in the treatment groups. However, immunohistochemical analysis of the kidneys of mice treated with 17 or 12 MBq 213Bi-IMP288 showed signs of tubular damage, indicating nephrotoxicity. Conclusion: To our knowledge, this study shows for the first time that PRIT with TF2 and 213Bi-IMP288 is feasible and at least as effective as 177Lu-IMP288. However, at higher doses, kidney toxicity was observed. Future studies are warranted to determine the optimal dosing schedule to improve therapeutic efficacy while reducing renal toxicity.

Project description:Objective We have previously shown that expression of the CEACAM1 long isoform (CC1-L) in metastatic colorectal cancer (CRC) cells results in significant inhibition of liver metastasis via Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Yet, despite recent advances in identifying molecules involved in the CC1-L inhibition of metastasis, much remains to be elucidated regarding the molecular mechanisms orchestrating this pathway. Design We performed an untargeted transcript profiling and a phosphokinase screen between CC1-L-expressing and non-expressing (CT) CRC cells. Identified targets were validated in vitro and in vivo for their involvement in signaling and invasion or metastasis. We validated our conclusions in CRC patient cohorts for time to metastasis development and long-term survival. Results Untargeted transcript profiling revealed high Decorin (Dcn) expression in CC1-L-expressing cells versus CT cells. Decorin was detected at the peri-endothelial layers of large blood vessels and in liver stellate cells. In metastatic lesions, it was expressed in pericyte-like cells covering capillary endothelium. Phosphokinase differential screening revealed reduced Ephrin type-A receptor 2 (EphA2) expression and activity in CC1-L- versus CT-expressing cells. Treatment of CT cells with recombinant Dcn led to decreased migration and invasion and decreased EphA2-mediated Erk and Akt signaling. CRC patients exhibiting high CC1 and DCN expression, in combination with low EPHA2 expression, benefit from longer 10-year survival than those with high EPHA2 expression. Conclusion CC1-L expression in poorly differentiated CRC inhibits liver metastasis through increased Decorin expression and EphA2-mediated signaling. Quadriplicate samples of each mouse colon cancer cell lines (control cells versus those expressing either short or long isoform of CEACAM1) have been used for RNA extraction

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Divergent roles of CD44 and carcinoembryonic antigen in colon cancer metastasis.

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Divergent roles of CD44 and carcinoembryonic antigen in colon cancer metastasis.

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