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. 2010 Apr;176(4):1619-28.
doi: 10.2353/ajpath.2010.090467. Epub 2010 Feb 11.

Serum cellular apoptosis susceptibility protein is a potential prognostic marker for metastatic colorectal cancer

Chin-Shaw Stella Tsai  1 , Hung-Chang Chen, Jai-Nien Tung, Shung-Sheng Tsou, Tang-Yi Tsao, Ching-Fong Liao, Ying-Chun Chen, Chi-Yuan Yeh, Kun-Tu Yeh, Ming-Chung Jiang
Affiliations

Serum cellular apoptosis susceptibility protein is a potential prognostic marker for metastatic colorectal cancer

Chin-Shaw Stella Tsai et al. Am J Pathol. 2010 Apr.

Abstract

Colorectal cancer has high rates of recurrence and metastasis. Many patients with similar histopathological features show significantly different clinical outcomes, and these differences are primarily related to metastases undetected by current diagnostic methods. There is no useful serological marker for metastatic disease. We investigated the cellular apoptosis susceptibility (CSE1L/CAS) protein in comparison with carcinoembryonic antigen (CEA) as a marker for metastatic colorectal cancer. Using serum from 103 patients with stage I, II, III, and IV disease, CSE1L was detected in 36.0% (9 of 25), 57.7% (15 of 26), 71.4% (30 of 42), and 88.9% (8 of 9) of patients, respectively; a pathological CEA level was found in 16.0% (4 of 25), 42.3% (11 of 26), 47.6% (20 of 42), and 77.8% (7 of 9) of patients, respectively; a combined CSE1L/CEA assay was detected in 48.0% (12 of 25), 65.4% (17 of 26), 88.1% (37 of 42), and 100% (9 of 9) of patients, respectively. Lymphatic metastasis is an important predictor of poor prognosis and crucial for determination of therapeutic strategy. Serum CSE1L was detected in 74.5% (38 of 51) of patients with lymph node metastasis, whereas a pathological CEA level was found in only 52.9% (27 of 51) of the same patients (P < 0.001); the combined CSE1L/CEA assay increased sensitivity to 90.2% (46 of 51). Animal experiments showed CSE1L reduction in B16-F10 melanoma cells correlated with decreased metastasis to the colorectal tract in C57BL/6 mice. These results indicate that assay of serum CSE1L may facilitate diagnosis of colorectal cancer lymphatic metastases; furthermore, CSE1L is a possible therapeutic target.

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Figures

Figure 1
Figure 1
Vesicle-like staining of CSE1L in HT-29 colorectal cancer cells. The cellular distribution of CSE1L in HT-29 cells was analyzed by immunofluorescence with clone 24 anti-CSE1L antibodies. Note that in addition to granule-like staining in the perinuclear areas, vesicle-like staining was observed in the cytoplasm near the cell membrane and in cell protrusions (arrowheads). Scale bar = 10 μm.
Figure 2
Figure 2
CSE1L staining in the gland lumen of colorectal cancer tissue. Distribution of CSE1L in metastatic colorectal cancer tissue was analyzed by immunohistochemistry with clone 3D8 anti-CSE1L antibodies. CSE1L staining was seen in the stroma (C, arrowhead) and gland lumen (D–F, arrows) of tissues. MMP-2 is a secretory protein, and its distribution was analyzed as the control. Positive staining for MMP-2 was also observed in the stroma (A, arrowhead) and gland lumen (B, arrows) of colorectal cancer tissue. Note the heavy staining of MMP-2 and CSE1L in large and cloud-like clumps in the gland lumen. Scale bars = 50 μm.
Figure 3
Figure 3
CSE1L protein in sera of patients with metastatic colorectal cancer. The presences of secretory CSE1L in serum of patients with metastatic colorectal cancer were evaluated by immunoblotting with anti-CSE1L antibodies. Wells loaded with the B16-F10 total cell lysate (lane 1) and conditioned medium collected from serum-starved B16-F10 cells (lane 2) were used as controls. Each well was loaded with 15 μl of serum sample or with 50 μl of conditioned medium collected from serum-starved B16-F10 cells. Note the sharp and intense CSE1L protein bands in wells loaded with sera from patients with metastatic colorectal cancer.
Figure 4
Figure 4
The relative levels of CSE1L and CEA associated with the colorectal cancer stages. The concentrations of CSE1L and CEA in sera from patients with colorectal cancer were measured by enzyme-linked immunosorbent assay and a CEA detection kit, and are shown by dot-plots as indicated. The line in each stage indicates the median value of the data, and a cross indicates the mean value of the data.
Figure 5
Figure 5
Reduced CSE1L expression correlated with decreased metastasis of B16-F10 cells to the colorectal tract in C57BL/6 mice. A: Expression levels of CSE1L in B16-EV and B16-anti-CSE1L cells were analyzed by immunoblotting with anti-CSE1L antibodies. Levels of β-actin were assayed with anti-β-actin antibodies as the control. B: Reduced CSE1L expression correlated with decreased tumor cell metastasis to the colorectal tract. *P = 0.041 compared with the number of metastases for mice injected with B16-EV control cells. The upper photograph is representative of tumors in the colorectal tract (arrowheads) and lungs (arrows). C: Reduced CSE1L expression decreased mortality of C57BL/6 mice injected with B16-F10 cells. *P = 0.022 compared with mortality of mice injected with B16-EV cells. There were three experimental groups, with each group including 11 mice injected with B16-EV cells and 11 mice injected with B16-anti-CSE1L cells. A total of 66 mice were used. Metastatic tumors in the colorectal tract were counted 25 days after injection. Eleven mice injected with B16-EV cells and six mice injected with B16-anti-CSE1L cells died 3 weeks after injection. Six mice (three injected with B16-EV cells and three injected with B16-anti-CSE1L cells) did not develop tumors. These mice, as well as the mice that died 3 weeks after injection, were excluded from calculations of tumor metastasis.
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