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Growth Factor Levels in the Blood of Patients Undergoing Radiation Therapy for Epithelial Cancer

ABSTRACT: RATIONALE: Measuring levels of transforming growth factor-beta (TGF-beta) in the blood of patients with epithelial cancers (head and neck, lung, breast, colorectal, and prostate) may help doctors predict how patients will respond to treatment with radiation therapy. PURPOSE: This research study is measuring levels of TGF-beta in patients with epithelial cancers who are undergoing radiation therapy.

DISEASE(S): Prostatic Neoplasms,Lung Cancer,Colorectal Cancer,Head And Neck Neoplasms,Prostate Cancer,Head And Neck Cancer,Breast Neoplasms,Lung Neoplasms,Breast Cancer

PROVIDER: 2072028 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Most available CRC cell lines have lost their TGF-beta response through the acquisition of mutations either in TGF-beta type II receptor (TGFBR2) or the intracellular mediator SMAD4 (Reviewed in Markowitz et al. 2002). To study the effect of TGF-beta in CRC epithelial cells, we restored wild-type TGFBR2 expression in the CRC cell line LS174T (LS). Ls174T cells are mutant for beta-catenin and therefore exhibit constitutive Wnt activity, which results in the expression of a genetic profile similar to that of intestinal epithelial progenitor cells (van de Wetering, Sancho et al. 2002). They thus reflect tumor cells at the initial stages of tumorogenesis. In addition, Ls174T cells bear mutations in the TGF-beta receptor II (TGFBR2) sequence at the BATRII locus (Grady and Markowitz 2002). This mutation gives rise to a non-functional truncated form of the receptor lacking the transmembrane domain and the serine-threonine kinase domain (Parsons, Myeroff et al. 1995). We generated inducible clones of Ls174T cells, where the expression of TGFBR2 could be controlled at will by the presence or absence of doxycycline (LSTGFBR2 cell line). Re-expression of wild-type receptor in Ls174T cells (LSTGFBR2) restored TGF-beta signalling resulting in strong phosphorylation of SMADs and activation of SMAD-binding reporter activity. Functionally, TGF-beta signalling in LSTGFBR2 resulted in a strong cytostatic response. By genome wide expression profiling using microarrays we investigated genes regulated by TGF-beta in this cell line. LsTGFBR2 inducible cells were generated by the Invitrogen T-Rex system following manufacturers instructions. LSTGFBR2 were seeded at 60% confluence in the presence or absence of Doxycycline and treated with TGF-M-NM-21 for 16 hours. Gene expression profiles were measured in duplicate using HG-U133 plus 2.0. We used RMA background correction, quantile normalization and RMA summarization (Gautier et al., 2004). A TGF-M-NM-2 response signature was obtained by selecting genes with limma P-value < 0.05 and at least two fold up-regulation in TGF-M-NM-2 treated LSTGFBR2 cells.

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Growth Factor Levels in the Blood of Patients Undergoing Radiation Therapy for Epithelial Cancer

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