Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer.
OBJECTIVE
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are important in tumor development and progression. MMP expression has been correlated with advanced clinical stage and poor survival in some tumors, but data for small-cell lung cancer (SCLC) are lacking. The aim of this study was to assess the expression of MMPs and TIMPs in SCLC and to evaluate their importance relative to standard prognostic factors.


METHODS
Expression of MMP-1, -2, -3, -9, -11, -13, and -14 and TIMP-1, -2, -3, and -4 was evaluated by immunohistochemistry (IHC). In situ hybridization was used to confirm expression of specific mRNAs. Clinical data collected included sex, tumor stage, performance status, weight loss, hematology (hemoglobin, WBC, platelets) and biochemistry (sodium, albumin, alkaline phosphatase, lactate dehydrogenase), treatment, and survival.


RESULTS
Samples from 46 patients were evaluated: 30 males, 16 females; 29 limited, 17 extensive stage; 35 Eastern Cooperative Oncology Group performance status 0-1. Positive IHC staining was evident for MMP-1 and -9 in 60% to 70% of tumor cells, and for MMP-11, -13, and -14 and TIMP-2 and -3 in 70% to 100% of tumor cells. Stromal staining of TIMP-1 to -3 was present in less than 30% of specimens. On multivariate analysis, only stage and decreased tumoral expression of TIMP-1 were significant for response (P =.043). Significant factors for survival were tumor stage (P =.0021); weight loss (P =. 013); and high tumor cell expression of MMP-3 (P =.077), MMP-11 (P =. 031), and MMP-14 (P =.019). MMP and TIMP expression did not differ significantly between stages.


CONCLUSIONS
MMPs and TIMPs are widely expressed in SCLC. Increased tumoral expression of MMP-3, -11, and -14 were independent negative prognostic factors for survival. The results support the evaluation of synthetic MMP inhibitors in patients with SCLC.
Michael
M
M
Department of Medical Biophysics, Laboratory Medicine and Pathobiology, and Biostatistics, Princess Margaret Hospital/Ontario Cancer Institute, The Toronto Hospital, and the University of Toronto, Ontario, Canada.
Babic
B
B
Khokha
R
R
Tsao
M
M
Ho
J
J
Pintilie
M
M
Leco
K
K
Chamberlain
D
D
Shepherd
F A
FA
D018288:Carcinoma, Small Cell / Q000201:enzymology* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000201:enzymology* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D012737:Sex Factors; D015996:Survival Rate; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D008666:Metalloendopeptidases; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4