transforming-growth-factor-beta and Neoplasm-Seeding

Metastatic, rather than primary tumours are responsible for ninety percent cancer deaths. Despite significant advances in the understanding of molecular and cellular mechanisms in tumour metastases, there are limitations in preventive treatment of metastatic tumours. Much evidence arising from laboratory and clinical studies suggests that growth factors and their receptors are implicated in cancer metastases development. We review the origin and production of growth factors and their receptors in all stages of cancer metastases including epithelial-mesenchymal transition, cancer cell invasion and migration, survival within the circulation, seeding at distant organs and metastatic tumour angiogenesis. The functions of growth factors and their receptors are also discussed. This review presents the efforts made in understanding this challenge to aid in the development of new treatment strategies for cancer metastases.

Topics: Angiopoietins; Animals; Apoptosis; Cell Movement; Epidermal Growth Factor; Epithelial-Mesenchymal Transition; ErbB Receptors; Glucose-6-Phosphate Isomerase; Hepatocyte Growth Factor; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Interleukin-8; Multienzyme Complexes; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Seeding; Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Phosphodiesterase I; Phosphoric Diester Hydrolases; Pyrophosphatases; Receptor, IGF Type 1; Receptors, Growth Factor; Ribonuclease, Pancreatic; Smad Proteins; Snail Family Transcription Factors; Transcription Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The purpose of these experiments was to identify growth factors produced during the formation of a peritoneal wound in relation to tumour cell seeding and stimulated growth in granulation tissue. Gelfoam(c) gelatin sponge was implanted in the mesenteric fan of nude mice to initiate the granulation process. Human HT29 colon carcinoma cells were inoculated intraperitoneally at various times after sponge implantation and tumour growth in granulation tissue was determined. RNA isolated from granulation tissue was used for polymerase chain reaction analysis of the expression of specific growth factors and receptors [vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-beta) and lysophosphatic acid (LPA)], and for microarray analysis of differentially expressed genes in early vs. late granulation tissue. Inflammatory cells infiltrated the sponge within 1 day, followed by fibroblasts and the formation of an extracellular matrix. Tumour cell inoculation at 8 h to 3 days after sponge implantation resulted in extensive tumour formation in all cases. Inoculation at 10-28 days resulted in focal tumour growth in only 16-33% of the sponges. Low amounts of VEGF, TGF-beta(1-3), TGF-beta RIII and LPA receptors 1,2 were detected in early granulation tissue, with increased expression from day 10. Microarray analysis identified additional differentially expressed genes that may stimulate tumour take and growth in early granulation tissue.

Topics: Animals; Female; Gelatin; Gene Expression; Granulation Tissue; Growth Substances; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Seeding; Oligonucleotide Array Sequence Analysis; Peritoneum; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

Topics: Animals; Bone Neoplasms; Breast Neoplasms; Cell Adhesion; Cell Movement; Chemokines; Embryo, Nonmammalian; Gene Expression Profiling; Genes, Tumor Suppressor; Humans; Neoplasm Metastasis; Neoplasm Seeding; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Receptors, Chemokine; Signal Transduction; Stem Cells; Transforming Growth Factor beta

Tenascin-C (TN-C) is an extracellular matrix glycoprotein expressed along epithelial/stromal boundaries during tissue remodelling events, such as those that occur during morphogenesis, wound healing, and tumour invasion. Using clinical specimens and a range of in vitro models that simulate homeostasis, wound healing, and malignant progression, this study sought to establish the patterns of TN-C expression in normal and neoplastic bladder and to determine the role of exogenous transforming growth factor beta-1 (TGFbeta-1), interleukin-4 (IL-4), basic fibroblast growth factor (bFGF), tumour necrosis factor alpha (TNFalpha), and interferon gamma (IFNgamma) in the induction of TN-C expression by bladder uro-epithelial cells. The findings indicate that normal urothelial cells may express TN-C, with both TGFbeta-1 and IL-4 able to induce expression. TN-C was not expressed in neoplastic urothelium, although both TN-C and TGFbeta-1 may be involved in tissue remodelling during papillary tumour formation and invasion. Furthermore, the urothelium of high-grade papillary tumours and carcinoma in situ specimens exhibited little TGFbeta-1 immunoreactivity, compared with the urothelium of low-grade tumours and normal specimens, suggesting an association between TGFbeta-1 expression and urothelial differentiation. A tumour invasion model, in which established bladder cancer cell lines were seeded onto a normal bladder stroma, corroborated the evidence from the clinical specimens and demonstrated that TN-C was strongly expressed around foci of stromal invasion. Thus, TN-C immunoreactivity may provide an additional tool in the assessment of early stromal invasion in bladder cancer.

Topics: Biomarkers, Tumor; Carcinoma in Situ; Carcinoma, Papillary; Cytokines; Humans; Immunoenzyme Techniques; Mucous Membrane; Neoplasm Proteins; Neoplasm Seeding; Organ Culture Techniques; Organoids; Tenascin; Transforming Growth Factor beta; Transforming Growth Factor beta1; Urinary Bladder; Urinary Bladder Neoplasms