The invasive phenotypes

Abstract

The expression of the invasive (I+ or I-) phenotypes determines cancer metastasis (M+ or M- phenotype). The invasive (I+ or I-) phenotypes can be divided according to time and site of expression into subphenotypes, which can be assessed separately. At various sites along the metastatic pathway the expression of the I phenotypes can be accompanied by the presence of uncontrolled growth (G+ phenotype) or its absence (G- phenotype). Various combinations of the I and G phenotypes determine the behaviour of metazoan or parasitic cells under normal, pathological non-neoplastic and neoplastic conditions. Although the G+I+M+ combination correlates with full malignancy, the sequence of events leading to the acquisition of these phenotypes during tumor development is not clear. Conditional invasion in experimental systems indicates that a tumor may be invasive and metastatic when part of its population temporarily expresses the I+ phenotype. These experiments further stress the importance of the tumor-host ecosystem for the regulation of the I phenotypes. As distinct from some parasites, the invasive morphotype of vertebrate cells cannot be simply identified. Nevertheless, within the tumor-host ecosystem morphological correlates of the activities of invasive cells may be recognized. They reflect one or more of the I+ functions, namely: motility; loss of homotypic cell-cell adhesion; establishment of alternative cell-substrate and heterotypic cell-cell adhesion; breakdown of extracellular matrices. These functions are not exclusive for I+ tumor cells, and neither are the molecular markers investigated so far. Oncogene activation leads mainly to G+ expression, and in this way serves as a signal amplifier for the I and M phenotypes. Attractive candidate molecular markers of I phenotypes are: regulators of hydrolase activities; cell-cell adhesion molecules; cell surface receptors. From data presently available, we hypothesize that invasion depends upon the balance between and I+ and an I- pathway, with both pathways being sensitive to stimulation inhibition.

Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

“…Many factors are involved in this process, such as Ca 2ϩ (24,44), chemoattractants (23), collagenases (48), cathepsins (43), MMPs (30), and serine protease (55). No direct evidence for V-ATPase expression at the plasma membrane for tumor invasion has been documented yet, but a relationship between pH cyt and invasion has been suggested.…”

Role of tissue stroma in cancer cell invasion

“…Metastasis may depend upon the specific site of the primary cancer. The frequency of distant metastasis from squamous cell carcinomas of the head and neck region depends upon the subsite of the primary cancer: cancers of the nasopharynx produce distant metastases more frequently (around 40%) than cancers of the glottis (around 5%) [4]. Orthotopic, as compared to ectopic (eg subcutaneous) implantation into immunosuppressed mice provides experimental evidence for the site specificity of invasion and metastasis.…”

“…When human colon cancer cells are implanted in the wall of the caecum [5,6] or when mammary carcinoma cells are implanted in the mammary fat pad [7] they invade, metastasize, and are relatively resistant to systemic treatment, in contrast to their subcutaneous counterparts [8]. In some tumour models, cells metastasize after subcutaneous injection but fail to metastasize upon intravenous injection, indicating that local host factors at the site of injection determine the metastatic capability of the cancer cells [4]. Cancer invasion is stimulated by wounding of the host tissue as demonstrated by rat colon adenocarcinoma cells that were transplanted into experimentally induced subcutaneous granulation tissue and in undisturbed subcutaneous tissue.…”

Metastasis-association of the rat ortholog of the human epithelial glycoprotein antigen EGP314

“…Tumor progression involves a series of events, frequently summarized as metastatic cascade, which includes detachment from the primary tumor, migration through the extracellular matrix, penetration through the basal membrane, adaptation to the circulation pressure, attachment to the endothelia of the vessel wall and settlement and growth in distant organs (Fidler and Radinsky, 1990;Mareel et al, 1991). To perform these distinct functions, metastatic cells frequently display an array of altered gene products (Bishop, 1991;Mareel et al, 1993), which include cell-cell and cell-matrix adhesion molecules (Evans, 1992;Glinsky, 1993;Zetter, 1993), matrixdegrading enzymes, their activators, inhibitors and receptors (Matrisian, 1992;Ossowski, 1992;Liotta et al, 1983;Magnatti et al, 1986).…”