Previous studies from this laboratory (Schroy, P., Rifkin, J., Coffey, R.J., Winawer, S., and Friedman, E. (Cancer Res., 50: 261-265, 1990; Schroy, P.C., Winawer, S., and Friedman, E. Cancer Lett., 48: 53-58, 1989) found that a 7-day treatment of the human colon carcinoma cell line HT29 with the differentiation agent hexamethylene bisacetamide (HMBA) induces both a 4-5-fold increase in transforming growth factor beta 1 (TGF beta 1) mRNA levels and reduced tumorigenicity in vivo.
The mRNA was localized to cancer cells with no labelling of stromal cells, although in a small number of cases scanty staining for TGF-beta 1 protein had been observed in stromal cells.
Expression of c-fos followed the TGF-beta 1 pattern, whereas no difference could be seen in c-jun expression in cancer as compared with BPH and normal prostate.
These results suggest that cancer stroma formation involves induction of similar fibroproliferative growth factors (TGF-beta 1 and CTGF) as wound repair.
Removal of fetal calf serum (FCS) from the culture medium or addition of forskolin or phorbol ester (TPA) also induced rapid elevation of aromatase mRNA and switching to exon 1c, whereas TGFbeta almost abolished the expression, suggesting that cancer cells might secret forskolin- or TPA-like stimulatory factors, or consume TGFbeta-like inhibitory factors in serum for expression of aromatase mRNA.
It is therefore possible that predisposition to atherosclerosis, bone diseases or various forms of cancer may be correlated with the presence of particular alleles at the TGFB1 locus.
To analyse the TGF-beta response in neuroblastoma, the expression of TGF-beta1 and TGF-beta type I, II and III receptor genes was investigated in 61 cancer samples by means of reverse transcription polymerase chain reaction.
Transforming growth factor beta1 (TGFbeta) simultaneously induces the expression of fibronectin, fibronectin receptor, laminin, and laminin receptor (alpha6beta1 integrin) in the human colon cancer cell line Moser (Int J Cancer, 57:742, 1994).
To our knowledge these are the first data to demonstrate reversal of activin and TGF-beta1 effects in thyroid malignancy and to demonstrate changes of the type Ib activin receptor expression in thyroid malignancy.
The five-year survival rate among patients whose cancer had high levels of microsatellite instability was 74 percent in the presence of a mutated gene for the type II receptor for TGF-beta1 and 46 percent if the tumor did not have this mutation (relative risk of death, 2.90; 95 percent confidence interval, 1.14 to 7.35; P=0.03).
Northern blot analysis revealed 3-fold and 4-fold increases (p < 0.05) in TGF-beta1 and CTGF mRNA levels, respectively, in esophageal cancer in comparison with normal controls, whereas TbetaR-I mRNA levels were significantly decreased and TbetaR-II mRNA levels were unchanged in the cancer samples.
In the present study, we sought to determine whether sequestration of endogenous TGFbeta by the expression of a soluble TGFbeta type III receptor (sRIII), can reduce malignancy in human carcinoma cells and whether the tumor-suppressive activity of sRIII is associated with the inhibition of angiogenesis.
We speculate that other factors, including additional polymorphisms of the TGF-beta1 gene, the status of TGF-beta1 receptors, the complex cytokine network, differential responsiveness of cells to the stimuli, and the status of the precancer/cancer genome, may play a role in development of invasive cervical cancer.
It was shown that, in NSCLC: (1) tumor stroma inflammatory cells are mainly TIL (approximately 2/3) (among them, 80 % are T-cells) and TAM (approximately 1/3), with almost no natural killer (NK) cells, and a few dentritic cells; (2) TAM and TIL are poorly replicating, but mainly recruited to the tumor stroma; (3) more than half TAM show an antibody-dependent cytotoxic potential, and one third of T-cells are TIA-1 positive CD8 activated cytotoxic lymphocytes; (4) cancer cells from only a few tumor express HLA class I and II antigens; (5) TAM production of cytotoxic cytokines [interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha)] and of transforming growth factor-beta1 (TGF-beta1) is low, in contrast to their strong release of platelet-derived growth factor (PDGF).
Germ-free TGF-beta1-deficient mice are free of inflammation, hyperplasia, and cancer, but when reintroduced into a Helicobacter hepaticus-containing specific pathogen-free room, these lesions reappear.
HHT types 1 and 2 are caused by loss of function mutations in ENG and ACVRL1; polymorphisms in TBRI and TGFB1 are also associated with altered risks for cancer and cardiovascular diseases.
In vivo studies on human colon adenocarcinoma showed decreased transforming growth factor-beta1 (TGF-beta1) antiproliferative cytokine content in tumour tissue related to malignancy progression, with a corresponding decrease in lipid peroxidation aldehydic end-product, 4-hydroxynonenal (HNE).
A decreased expression of TGFbeta receptors (TbetaR) has been associated with loss of TGFbeta sensitivity and enhanced tumor progression in many types of cancer.
Matrix metalloproteinase-21 is expressed epithelially during development and in cancer and is up-regulated by transforming growth factor-beta1 in keratinocytes.