Serum markers of matrix turnover as predictors for the evolution of colorectal cancer metastasis under chemotherapy

Abstract

Connective tissue turnover plays a prominent role in tumour growth and metastasis. We followed serum levels of seven connective tissue parameters in 37 patients with colorectal cancer metastatic to the liver prior to and during chemotherapy. Serum samples with episodes of tumour control (n ¼ 112) showed an increase of matrix metalloproteinase-2 (MMP-2) (Pp0.01) and a decrease of tissue inhibitor of MMPs (TIMP-1) levels (Pp0.01), while serum samples with episodes of tumour progression displayed the reverse pattern (Pp0.01 and Pp0.05, resp.). The ratio of circulating MMP-2/TIMP-1 was also significantly higher in episodes of tumour control vs tumour progression and prior to treatment (Pp0.0001). We conclude that serum MMP-2 appears to reflect tumour resorption, while serum TIMP-1 may mirror tumour expansion. Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a central role in benign and malignant matrix remodelling (Kähäri and Saarialho-Kere, 1999;Nagase and Woessner, 1999). MMP-2 and MMP-9 (gelatinases A and B, resp.) degrade basement membrane collagen as well as denatured collagens (gelatin). MMP activity is tightly regulated (1) on the level of transcription, (2) on the level of proteolytic activation of the pro-MMPs, (3) by the tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) and (4) by their strict compartmentalisation in cell membrane domains. Enhanced local expression and activity of MMPs and low levels of inhibitory TIMPs correlate with tumour growth and metastasis (Zeng et al, 1995(Zeng et al, , 1996Murray et al, 1996). However, the findings on circulating MMP-and TIMP levels in patients with metastatic colorectal tumours are unclear (Holten-Andersen et al, 2000;Pellegrini et al, 2000;Ylisirnio et al, 2000).CEA and CA 19-9 have been previously shown to predict tumour growth in patients with liver metastasis treated by chemotherapy (Hanke et al, 2001). However, there exist no follow-up data with serum connective tissue markers to predict treatment response or nonresponse in these patients. Colorectal cancer metastatic to the liver is particularly suited to validate novel markers, since the condition is characterised by a large and defined tumour burden. MATERIALS AND METHODSWe studied 37 consecutive patients (29 men, eight women, age 42 -76 years, mean 62 years) with colorectal carcinoma metastatic to the liver. Primary carcinoma was confirmed histologically. Histological confirmation was also obtained for synchronous liver metastasis. In case of metachronous liver metastasis, histological confirmation was only pursued when imaging techniques (spiral computerised tomography (CT) of the abdomen or MRT of the liver) did not show clear results. Patients received first-line chemotherapy, consisting of a weekly 1 -2 h infusion of folinic acid (500 mg m À2 ) followed by a 24-h infusion of 5-fluorouracil (2600 mg m À2 ). One cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 16 patients received additional biweekly oxaliplatin (85 mg m À2 ) and three patients ad...

Collagen and tissue turnover as a function of age: Implications for fibrosis

“…Several serum assays have been developed to measure ECM turnover in experimental animals and man. There are numerous reports on components of the ECM and particularly different types of collagens and collagen fragments that circulate in serum and that are elevated in fibrotic diseases of joints and bone (10)(11)(12), in systemic sclerosis (13;14), in metastatic cancer (15) and in fibrosis of lungs (16), kidneys (17;18), and liver (3;18-23). However, in all these studies it has been difficult to assign the measured antigen levels in blood either to ECM production and deposition (fibrogenesis), to ECM degradation and removal (fibrolysis), or merely to enhanced ECM turnover.…”

Serum connective tissue markers as predictors of advanced fibrosis in patients with chronic hepatitis B and D

“…Immune complexes were separated from serum using magnetic particles covered with monoclonal anti-fluorescein. The assays were developed for the BA-YER IMMUNO 1 TM immunoassay system and validated in a large cohort of liver patients and healthy subjects (18)(19)(20)(21). Serum samples were stored at -80°C until use.…”

“…In this study, we assessed the predictive value of nine fibrosis markers derived from the ECM (18)(19)(20)(21) as well as biochemical markers of liver function and inflammation in well-defined cohorts of adult patients with HBeAg-positive and -negative chronic hepatitis B and chronic hepatitis D. We could show that, compared to all other markers and their combinations, the combination of two of these markers, tissue inhibitor of metalloproteinases-1 (TIMP-1) and hyaluronan, achieved the best prediction of fibrosis stage ≥F2, when matched to histological fibrosis, which was complemented with spleen size and platelet count to minimize sampling error.…”

Expression of PCNA and CD44mRNA in colorectal cancer with venous invasion and its relationship to liver metastasis

“…Venous invasion of cancer cells was the first step of neoplasm's liver metastasis [29] . However, in clinical cases, venous invasion by histological detection was not definitely related to liver metastasis.…”