High levels of transforming growth factor beta 1 in patients with colorectal cancer: Association with disease progression

Tsushima, Hirofumi; Kawata, Satoshi; Tamura, Shinji; Ito, Nobuyuki; Shirai, Yoshio; Kiso, Shinichi; Imai, Yumiko; Shimomukai, Hiromi; Nomura, Yasuharu; Matsuda, Yasuo; Matsuzawa, Yūji

doi:10.1053/gast.1996.v110.pm8566583

Cited by 268 publications

(165 citation statements)

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“…Consistent with this notion, increased TGFb1 expression by tumor cells correlated with tumor progression in non-small cell lung carcinoma (NSCLC), colorectal cancer, prostate cancer, and gastric carcinoma [13][14][15][16]. Additionally, intense TGFb staining has also been positively correlated with metastasis in breast carcinoma, prostate cancer, and colorectal cancer.…”

Section: Introductionmentioning

confidence: 62%

Roles of TGFβ in metastasis

2008

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The TGFβ signaling pathway is conserved from flies to humans and has been shown to regulate such diverse processes as cell proliferation, differentiation, motility, adhesion, organization, and programmed cell death. Both in vitro and in vivo experiments suggest that TGFβ can utilize these varied programs to promote cancer metastasis through its effects on the tumor microenvironment, enhanced invasive properties, and inhibition of immune cell function. Recent clinical evidence demonstrating a link between TGFβ signaling and cancer progression is fostering interest in this signaling pathway as a therapeutic target. Anti-TGFβ therapies are currently being developed and tested in preclinical studies. However, targeting TGFβ carries a substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. Additionally, clinical and experimental results show that TGFβ has diverse and often conflicting roles in tumor progression even within the same tumor types. The development of TGFβ inhibitors for clinical use will require a deeper understanding of TGFβ signaling, its consequences, and the contexts in which it acts.

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Section: Introductionmentioning

confidence: 62%

Roles of TGFβ in metastasis

2008

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“…30 Therefore, we determined the expression patterns of FHL2, TGF-b1 and a-SMA, and their respective localisation in the micromilieu of sporadic and HNPCC-associated microsatellite-instable colon cancer in vivo. Normal colon mucosa showed no significant FHL2 expression of stromal fibroblasts, a finding which was also described by a previous study.…”

Section: Discussionmentioning

confidence: 99%

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Gullotti

Czerwitzki

Kirfel

et al. 2011

Laboratory Investigation

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Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-b1 ligand and a-SMA. Myofibroblasts at the tumour invasion front co-expressed a-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-b1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-b1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-b. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-b1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas. Four and a half LIM domain protein-2 (FHL2) was first identified as a protein differentially expressed in human myoblasts and rhabdomyosarcoma cells, and thus named DRAL (downregulated in rhabdomyosarcoma LIM protein 1 ). FHL2 is a LIM-only protein with four complete and one N-terminal half LIM domains that mediate protein-protein interactions. 2 FHL2 associates with integrin receptors to form focal adhesion contacts and binds signal transducers such as b-catenin. 3-5 Triggered by lipid-induced signalling, such as sphingosine-1-phosphate, FHL2 translocates into the nucleus where it binds several transcription factors including serum response factor, AP1 and androgen receptor and functions as a coactivator or a corepressor to modulate gene expression. [6][7][8] We showed previously that FHL2 is strongly upregulated in mesenchymal cells of wounded skin, and demonstrated a function of FHL2 in myofibroblasts regulating their migration and contraction during cutaneous wound healing. 9 Furthermore, FHL2 is critically involved in matrix assembly allowing migration of cells into the wound area. 10 Analogous to wound healing invasive carcinomas generate a specialised tumour stroma and de...

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“…25 Alternatively, the production of immune-inhibitory cytokines, such as FAS-L, IL-10 or TGF-b may also explain the observed discrepancies in leukocyte infiltration. [26][27][28][29] Regarding the question as to which arm of the immune systems plays the most significant role in the antitumor effect, it is generally believed that the activation of tumor-specific, cytotoxic T cells plays a more prominent role than the leukocytes involved in innate immunity (eg NK cells). In the present study, we provided evidence that NK cells or NK-like T cells also play an important role.…”

Section: Discussionmentioning

confidence: 99%

Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis

Menon

Rhijn

Morreau

et al. 2004

Laboratory Investigation

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The efficacy of tumor cell-immune cell interactions depends on a number of factors, for example, the expression of HLA-I on tumor cells, the type of immune cell, the accessibility of tumor cells for immune cells and the expression of immunogenic epitopes. We assessed infiltration of CD4 þ , CD8 þ , CD56 þ and CD57 þ cells in the tumor epithelium, tumor stroma and advancing tumor margin of 93 colorectal carcinomas and correlated this to clinicopathological parameters, the expression of HLA-A and HLA-B/C on tumor cells, the presence of a basal membrane (BM)-like structure surrounding tumor nodules and the presence of microsatellite instability/ mutator phenotype (absent MLH-1 expression). The median intraepithelial CD4 þ , CD8 þ , CD56 þ and CD57 þ cell infiltrations were 3, 23, 0 and 0 cells/mm 2 tumor, respectively. HLA-A/BC expression by tumor cells was normal in 28/43%, heterogeneous in 59/48% and absent in 13/9% of the cases. A BM-like structure surrounding the tumor nodules was absent, present and thick in 47, 38 and 15% of the cases. Six cases lost MLH1 expression. There was a positive correlation between leukocyte infiltration in the three compartments for CD4 þ , CD8 þ , CD56 þ (partly) and CD57 þ (all Po0.05) cell infiltration. Intraepithelial CD8 þ cell infiltration inversely correlated with HLA-A (P ¼ 0.04) and HLA-B/C expression (P ¼ 0.04). Intraepithelial CD57 þ cell infiltration inversely correlated with HLA-B/C expression (P ¼ 0.04). Moreover, intraepithelial infiltration of CD8 þ and CD57 þ cells was inversely correlated to the presence of a BM-like structure (P ¼ 0.003 and 0.04, respectively). Uni-and multivariate analyses showed that a lower tumor stage (P ¼ 0.004) and marked infiltration of CD8 þ (P ¼ 0.04) and CD57 þ cells (P ¼ 0.05) at the advancing tumor margin were independent prognostic factors for a longer diseasefree survival. Loss of MLH1 expression was correlated with a significantly higher intraepithelial CD8 þ and CD57 þ cell infiltration. We conclude that infiltration of CD8 þ and CD57 þ cells are important prognostic factors in colorectal cancer. However, their interaction with tumor cells is inversely correlated to the presence of HLA-I on tumor cells and a thick BM-like structure around tumor islets. Our data indicate that NK cells might play an important role in the immune surveillance in colorectal cancer patients.

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High levels of transforming growth factor beta 1 in patients with colorectal cancer: Association with disease progression

Cited by 268 publications

References 4 publications

Roles of TGFβ in metastasis

Roles of TGFβ in metastasis

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis

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