Liver, Pancreas and Biliary TractLiver expression of matrix metalloproteases and their inhibitors in hepatocellular carcinoma
Introduction
The majority of hepatocellular carcinoma (HCC) patients show at the time of diagnosis advanced or unresectable disease. The prognosis is poor even for those patients who undergo resection. This is due to the recurrence rates, which are among the highest of any solid tumour, reaching 50% 2 years after resection [1], [2], [3]. In addition, HCCs are inherently chemotherapy-resistant tumours [4]. Metastatic recurrence is the main obstacle towards the improvement of treatment efficacy. Proteolytic enzymes of various classes participate in the degradation of the stromal connective tissue and basement membrane components, therefore facilitating tumour invasion and metastasis. However, some matrix components, particularly the interstitial collagens, are very resistant to proteolytic attacks, being degraded only by matrix metalloproteases (MMPs) [5].
The human MMP family currently consists of 28 members of homologous zinc-dependent endopeptidases, which can be divided into eight structural classes or, based on their substrate specificity and primary structure into the more familiar subgroups of collagenases (MMP-1, -8 and -13), gelatinases (MMP-2 and -9), stromelysins (MMP-3, -10 and -11), membrane-associated MMPs (MMP-14, -15, -16, -17, -23, -24 and -25) and other novel MMPs [6], [7], [8], [9]. MMPs are synthesized as inactive zymogens, being then activated predominantly pericellularly by other MMPs or by serine proteases. MMPs’ activity is specifically inhibited by the so-called tissue inhibitors of metalloproteases (TIMPs). Currently, four different TIMPs are known to exist: TIMPs-1, -2, -3 and -4. In addition, this enzymatic system has two additional aspects of relevance in cancer biology: MMPs are able to impact on tumour cell behaviour in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines [10], [11], [12], [13], [14], [15]. MMPs, by cleaving proapoptotic factors produce a more aggressive phenotype via generation of apoptotic resistant cells [16]. MMPs also regulate angiogenesis in cancer, positively through their ability to mobilize or activate proangiogenic factors [17], [18], and negatively via generation of angiogenesis inhibitors, such as angiostatin and endostatin, cleaved from large protein precursors [19], [20], [21]. On the other hand, it is now assumed that TIMPs are multifactorial proteins also involved in the induction of proliferation and in the inhibition of apoptosis [22], [23].
Several studies have suggested the significance of some MMPs in the malignant behaviour of HCC, such as MMP-2 [24], [25], [26], [27], [28], [29], [30], [31], MMP-7 [26], [32], MMP-9 [29], [31], [33], [34], [35], and MMP-14 (MT1-MMP) [29], [36], [37], [38]. These MMPs were associated with several indicative parameters of tumour aggressiveness and poor prognosis. However, the cellular type expressing each factor (tumour cell and/or peritumour stromal cell) was not specifically considered in HCCs. Likewise, there are few available data referring to the integrated expression of these factors in HCC.
The objectives of the present work are: (i) to evaluate the expression of several MMPs and TIMPs in HCCs by using the tissue microarray (TMA) technique, which allows us to integrate the biological aspects of this complex enzymatic expression in the morphological context of HCCs; (ii) to investigate their relationship with clinico-pathological and biological characteristics of the tumours; and (iii) to determine the correlation between the expressions of these proteins and overall survival.
Section snippets
Patient selection
The study population included 30 patients diagnosed with HCC at the University Hospital Central of Asturias in Oviedo, Spain, during a 13-year period (1989–2002) and before a program of liver transplantation was developed. The patients included in the study have been followed up at the same hospital since then.
All the cases were diagnosed on a clinical basis with imaging and pathological confirmation of the tumour. Patients showed limited nodular disease and associated cirrhosis, stage A in 24
Results
More than 600 determinations of cancer specimens from 30 patients with HCC and controls were performed on TMAs. Minimal internal variance of score data between duplicate tissue cores from the same patients was detected in the tissue arrays, showing a high agreement for each protein (r > 0.95 and p < 0.0001, for each protein). In the validation study there was a total concordance in the global expression, as well as in the intensity of immunostaining, for each MMP and TIMP between TMA cases and the
Discussion
In the present study we have described new findings on the expressions of MMPs and TIMPs in HCC, together with an important expression by tumour stromal cells, as well as their clinical relevance. It is known that the expression of MMPs in neoplastic tissues is high due to a paracrine regulation by growth factors and cytokines secreted by either tumour or stromal cells [44]. Nevertheless, the high expressions of MMPs and TIMPs by HCCs tissues may be also because of the interplay between
Conflict of interest statement
None declared.
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