Recent findings have produced great strides in developing an understanding of the molecular events involved in processes necessary for tumor cell invasion and subsequent metastasis formation. This information has been useful in developing new targets for therapeutic intervention such as disruption of tumor cell attachment by peptide analogues of cell adhesion molecules and the use of protease inhibitors to limit extracellular matrix proteolysis required for tumor cell invasion. Future efforts must focus on how the events of cell attachment, matrix proteolysis, and cell migration are controlled and integrated. This requires a better understanding of the transcriptional controls and cell signaling mechanisms that are involved in these events. Preliminary findings suggest that cell-matrix interactions influence gene expression and that the protease inhibitor balance can greatly influence cell-matrix interactions. Therefore it appears that all three steps in the invasive process are linked and interdependent. While this complicates the study of these processes, it is our belief that understanding this interdependence is critical for further development of metastasis research.

Tumor Cell Interactions with the Extracellular Matrix During Invasion and Metastasis

Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in sp...

Matrix Metalloproteinases: Biologic Activity and Clinical Implications

Hepatocarcinogenesis is a slow process during which genomic changes progressively alter the hepatocellular phenotype to produce cellular intermediates that evolve into hepatocellular carcinoma. During the long preneoplastic stage, in which the liver is often the site of chronic hepatitis, cirrhosis, or both, hepatocyte cycling is accelerated by upregulation of mitogenic pathways, in part through epigenetic mechanisms. This leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomere erosion and telomerase re-expression, sometimes microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and emergence of hepatocellular carcinoma are associated with the accumulation of irreversible structural alterations in genes and chromosomes, but the genomic basis of the malignant phenotype is heterogeneous. The malignant hepatocyte phenotype may be produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of hepatocellular carcinoma. New strategies should enable these variants to be characterized.

Molecular pathogenesis of human hepatocellular carcinoma

Hepadnaviruses (hepatitis B viruses) cause transient and chronic infections of the liver. Transient infections run a course of several months, and chronic infections are often lifelong. Chronic infections can lead to liver failure with cirrhosis and hepatocellular carcinoma. The replication strategy of these viruses has been described in great detail, but virus-host interactions leading to acute and chronic disease are still poorly understood. Studies on how the virus evades the immune response to cause prolonged transient infections with high-titer viremia and lifelong infections with an ongoing inflammation of the liver are still at an early stage, and the role of the virus in liver cancer is still elusive. The state of knowledge in this very active field is therefore reviewed with an emphasis on past accomplishments as well as goals for the future.

Hepatitis B Virus Biology

The insulin-like growth factors (IGFs) are mitogens that play a pivotal role in regulating cell proliferation, differentiation, and apoptosis. The effects of IGFs are mediated through the IGF-I receptor, which is also involved in cell transformation induced by tumor virus proteins and oncogene products. Six IGF-binding proteins (IGFBPs) can inhibit or enhance the actions of IGFs. These opposing effects are determined by the structures of the binding proteins. The effects of IGFBPs on IGFs are regulated in part by IGFBP proteases. Laboratory studies have shown that IGFs exert strong mitogenic and antiapoptotic actions on various cancer cells. IGFs also act synergistically with other mitogenic growth factors and steroids and antagonize the effect of antiproliferative molecules on cancer growth. The role of IGFs in cancer is supported by epidemiologic studies, which have found that high levels of circulating IGF-I and low levels of IGFBP-3 are associated with increased risk of several common cancers, including those of the prostate, breast, colorectum, and lung. Evidence further suggests that certain lifestyles, such as one involving a high-energy diet, may increase IGF-I levels, a finding that is supported by animal experiments indicating that IGFs may abolish the inhibitory effect of energy restriction on cancer growth. Further investigation of the role of IGFs in linking high energy intake, increased cell proliferation, suppression of apoptosis, and increased cancer risk may provide new insights into the etiology of cancer and lead to new strategies for cancer prevention.

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Role of the insulin-like growth factor family in cancer development and progression

In 187 node-negative breast cancers, the expression of laminin receptors and collagenase IV was directly related in 52% of cases, independently of pathological (tumor size and histology) and biological (estrogen receptors and proliferative activity) features. Moreover, the presence of laminin receptors and collagenase IV did not appear to influence tumor proliferative activity, evaluated as 3H-thymidine labelling index. In this case series, relapse-free survival and overall survival at 6 years were significantly affected by tumor size, hormone receptor status and proliferative activity. Conversely, high levels of laminin receptors and collagenase IV failed to influence relapse-free or overall survival, whereas they were strong indicators of local-regional diffusion of the disease.

Laminin receptors, collagenase IV and prognosis in node-negative breast cancers.

Prognosis of gastric carcinoma revealed by interactions between tumor cells and basement membrane

Invasion and metastasis requires a series of interactions between malignant cells and the extracellular matrix (ECM). Antigen markers that relate to these interactions were evaluated for prognostic correlation in human hepatocellular carcinoma. Basement membrane type IV collagen (cIV), type IV collagenase (cIVase), laminin, and laminin receptors (LRs)--all ECM antigens previously proposed to be modulated in association with tumor aggressiveness--were immunohistochemically investigated in 30 cases of hepatocellular carcinomas (HCCs). The pattern of antigen expression was correlated with 1) 36 months' clinical follow-up and 2) the pathologic grade. As a means of estimating the proliferation fraction, an additional antigen, Ki67, was also studied in this series. There were major differences in the distribution of cIV and laminin, and in the quantity of cIVase-, LR-, and Ki67-positive cells associated with grade and prognosis. A smaller quantity of cIV and laminin and a higher number of cIVase-, LR-, and Ki67-positive cells were detected in the poorly differentiated compared with the well-differentiated HCCs. The tumors with lower immunoreactivity for cIV and laminin components accompanied by a higher number of cIVase-, LR-, and Ki67-positive cells fall into a group with the poorest overall survival (P less than 0.006). The panel of antigens is proposed as a useful prognostic tool for evaluating HCC tumor aggressiveness.

Evaluation of hepatocellular carcinoma aggressiveness by a panel of extracellular matrix antigens.

Eleven cases of primary pancreatic adenocarcinomas have been investigated histochemically, immunohistochemically and with electron-microscopy. Endocrine-paracrine (EP) cells were present in six of these tumours. In one case numerous 5HT-enterochromaffin cells (EC) of the intestinal type and a few somatostatin immunoreactive D cells were found. Two cases contained insulin-immunoreactive cells and another case displayed glucagon-IR elements. In the remaining two cases argyrophilic cells were present. These findings demonstrate that polypeptide hormone or amine production is not restricted to islet cell tumours. It is suggested that both endocrine and exocrine components of the tumours studied might have derived from a common precursor.

Endocrine-paracrine cells in pancreatic exocrine carcinomas.

Thirty-two cases of primary liver neoplasms comprising 12 benign, 15 malignant, and 5 cases with equivocal histopathological features between benign and malignant have been investigated using monoclonal antibody (MoAb) Ki 67, which reacts with a nuclear protein expressed in the G1, G2, S, and M phases of the cell cycle.



The Ki67 score (positive cells/total neoplastic cells) seems to correlate to the classes of lesions tested. In the hepatocellular carcinoma (HCC) group, the percentage of labelled nuclei, ranging from 15 to 50 per cent, showed a good correlation with Edmondson-Steiner's histological tumour grade.



A percentage of positive cells similar to that of the proved low-grade HCCs was detected in the five neoplastic lesions in which the routine histopathological criteria of malignancy were not fulfilled. The benign neoplasms showed a very low growth fraction, similar to that of normal or cirrhotic tissues.



The use of the Ki 67 score seems to offer useful information about the biological behaviour of some liver masses and may help in the differential diagnosis of hepatocellular adenoma versus carcinoma.

A. M. Mancini

Papers

Laminin receptors, collagenase IV and prognosis in node-negative breast cancers.

Prognosis of gastric carcinoma revealed by interactions between tumor cells and basement membrane

Evaluation of hepatocellular carcinoma aggressiveness by a panel of extracellular matrix antigens.

Endocrine-paracrine cells in pancreatic exocrine carcinomas.

Primary liver neoplasms: evaluation of proliferative index using MoAb Ki67.