Summary The matrix metalloproteinases (MMPs) are perceived as essential for tumour invasion and metastases. The purpose of this study was to determine the expression and cellular localisation of the 92 kDa type IV collagenase (MMP-9) protein and mRNA in human colorectal cancer (CRC). In CRC and matched normal mucosa specimens from 26 CRC patients, Northern blot hybridisation and Western blot analyses provide convincing evidence that MMP-9 is expressed in greater quantities in CRC than in normal tissue. The MMP-9 tumour to normal mucosa fold-increase (T/N) was 9.7+7.1 (mean+s.d.) (P<0.001) for RNA and 7.1 + 3.9 (P< 0.001) for protein. The sites of MMP-9 mRNA and protein synthesis were colocalised in tumour stroma by in situ hybridisation and immunohistochemistry in 26 CRC samples. Both MMP-9 mRNA and protein signals were strongest in the population of stromal cells concentrated at the tumour-stroma interface of an invading tumour. Furthermore, MMP-9-positive cells were identified as macrophages using an antimacrophage antibody (KP1) in serial sections from ten CRC samples. Given the persistent localisation of MMP-9-producing macrophages to the interphase between CRC and surrounding stroma, our observations suggest that MMP-9 production is controlled, in part, by tumour-stroma cell interactions. Further studies are needed to determine the in vivo regulation of MMP-9 production from infiltrating peritumour macrophages.Keywords: 92 type IV collagenase; matrix metalloproteinase; colorectal cancer; macrophage Crucial steps in tumour invasion and metastases are the breaching of the basement membrane (BM) and degradation of the extracellular matrix (ECM) Matrisian, 1992). These processes are likely to involve numerous proteolytic enzymes, including matrix metalloproteinases (MMPs), a family of extracellular matrix-degrading enzymes . To date, at least 14 members of the MMP family have been described by substrate specificity (Birkedal-Hansen, 1995). Based on substrate preference, MMPs can be subclassified into interstitial collagenases (MMP-1, MMP-8 and MMP-13), type IV collagenases/ gelatinase (MMP-2 and MMP-9), stromelysins (MMP-3 and MMP-10), membrane-type MMPs [MT-MMP1 (Sato et al., 1994), MT-MMP2 (Will and Hinzmann, 1995), MT-MMP3 (Takino et al., 1995) and MT-MMP4 (Puente et al., 1996)]. However, several MMPs including, stromelysin 3 (MMP-11) (Noel et al., 1995) and macrophage metalloelastase (Woessner, 1994;Birkedal-Hansen, 1995) do not appear to belong to any one group.An important role for MMPs in invasion and metastases is supported by studies demonstrating a correlation between elevated MMP levels and the metastatic phenotype in cell cultures (Ballin et al., 1988;Moll et al., 1990; TurpeenniemiHujanen et al., 1985;Yamagata et al., 1988), animal models (Nakajima et al., 1990) and several human tumours (Muller et al., 1991;McDonnell et al., 1991;Hamdy et al., 1994;Levy et al., 1991;Stearns and Wang, 1993;Rao et al., 1993;Yoshimoto et al., 1993;Kossakowska et al., 1993;Brown et al., 1993;Naylor et al., 1994)...

Summary To examine the hypothesis that colorectal carcinomas with and without TP53 mutations may be characterised by aetiological heterogeneity, we analysed a group of 107 patients with primary Dukes' C colorectal cancer seen at the Memorial Sloan-Kettering Cancer Center (MSKCC) from 1986 to 1990. We assessed p53 overexpression using the monoclonal antibody PAb 1801, and identified 42 (39%) patients displaying p53-positive phenotype, defined as >25% of positive cells. Patients with two or more first-degree relatives with cancer had an odds ratio (OR) of 2.9 (95% CI 1.0-8.3) for p53 overexpression in comparison with those without a family history of cancer (trend test, P = 0.11). A possible association between body weight and p53 overexpression was observed. The ORs were 1.9 for the second quartile, 1.9 for the third quartile and 3.4 for the highest quartile in comparison with the lowest quartile (trend test, P = 0.06). No association between occupational physical activity, smoking, drinking, parity and p53 overexpression was identified. The results suggest that p53 overexpression may be related to genetic predisposition to colorectal cancer, and p53-positive and p53-negative colorectal cancers may be controlled by different aetiological pathways.Keywords: body weight; colorectal neoplasms; family history; p53/protein; risk factors Colorectal cancer (CRC) is the second most common malignancy of both sexes in developed countries . A total of 394 000 deaths are estimated to occur annually for colorectal cancer, making it the third most important cause of cancer mortality in the world . It is also a major public health problem in the United States, with an estimated 149000 new cases diagnosed in 1994, including 107 000 of colon cancer and 42 000 of rectum cancer. The incidence ranks the third in males and the second in females in the United States (American Cancer Society, 1994). Epidemiological studies show that increased risk of colorectal cancer may be associated with both genetic and environmental factors (Potter et al., 1993). For the genetic component of CRC, two major types of CRC predisposition have been identified: familial adenomatous polyposis (FAP), which is believed to account for 1% of CRC cases, and hereditary non-polyposis colorectal cancer (HNPCC), which is considered to explain about 4-15% of CRC cases (Peltomaki et al., 1993 (Marks et al., 1991;Cunningham et al., 1992;Vahakangas et al., 1992;Dalbagni et al., 1993;Cordon-Cardo et al., 1994;Jacquemier et al., 1994). TP53 mutational spectra can point to particular leads in the aetiology and carcinogenesis of cancer (Harris, 1993 (Field et al., 1991;Brachman et al., 1992), oesophageal (Hollstein et al., 1991) and bladder cancers (Spruck et al., 1993;Zhang et al., 1994a). It has also been related to the ageing in prostatic adenocarcinoma (Zhang et al., 1994b) and associated with exposures to ultraviolet light in squamous cell carcinoma (Brash et al., 1991), and to aflatoxin exposure and hepatitis B virus (Hsu et al., 1993) in hepatocellular carcinomas...

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