MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma.
OBJECTIVE
Macrophage inhibitory cytokine-1 (MIC-1) is a divergent member of the tumor growth factor beta (TGF-beta) superfamily. Several observations suggest that it plays a role in colorectal carcinoma (CRC). In particular, MIC-1 is markedly up-regulated in colorectal cancers as well as in premalignant adenomas. This study examines the relationship of serum MIC-1 levels and genotypes to clinical and pathologic features of colonic neoplasia.


METHODS
We confirmed the presence of MIC-1 in CRC tissue and the cell line CaCo-2. The normal range for serum MIC-1 levels was defined in 260 healthy blood donors, and the differences between normal subjects and 193 patients having adenomatous polyps or CRC were then determined. In a separate cohort of 224 patients, we evaluated the relationship of MIC-1 serum level and genotype to standard tumor parameters and outcome measures.


RESULTS
MIC-1 was expressed in CRC tissue and the cancer cell line CaCo-2. There was a progressive increase in serum MIC-1 levels between normal individuals [mean (M) = 495 pg/ml, SD = 210), those with adenomatous polyps (M = 681 pg/ml, SD = 410), and those with CRC (M = 783 pg/ml, SD = 491)]. Serum MIC-1 level was correlated with the extent of disease so that the levels were higher in patients with higher Tumor-Node-Metastasis stage. There were significant differences in time to relapse and overall survival between subjects with different MIC-1 levels and genotypes.


CONCLUSIONS
This study identifies a strong association between MIC-1 serum levels and neoplastic progression within the large bowel. We suggest that the measurement of serum MIC-1 levels and determination of MIC-1 genotype may have clinical use in the management of patients with CRC.
Brown
David A
DA
Centre for Immunology, St. Vincent's Hospital and University of New South Wales, Sydney NSW, Australia.
Ward
Robyn L
RL
Buckhaults
Philip
P
Liu
Tao
T
Romans
Katharine E
KE
Hawkins
Nicholas J
NJ
Bauskin
Asne R
AR
Kinzler
Kenneth W
KW
Vogelstein
Bert
B
Breit
Samuel N
SN
D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D018256:Adenomatous Polyps / Q000378:metabolism; D000483:Alleles; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000097:blood* / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D055436:Growth Differentiation Factor 15; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D009362:Neoplasm Metastasis; D011379:Prognosis; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation
D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D016212:Transforming Growth Factor beta