Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells

Kinoshita, Koichi; Nakagawa, Koji; Hamada, Junichi; Hida, Yasuhiro; Tada, Mitsuhiro; Kondo, Satoshi; Moriuchi, Tetsuya

doi:10.3892/ijo_00000738

Cited by 22 publications

(20 citation statements)

References 32 publications

(44 reference statements)

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“…Apart from our results, Pessina et al showed that CM from human skinderived fibroblasts treated with Paclitaxel (a chemotherapeutic drug) is a potent inhibitor of tumor cells in vitro (13). In addition, other groups showed that CM from CAFs has a growth-promoting effect on tumor cells due to factors secreted in the culture medium (14,15). Among these factors, IL-6, TGFbeta, COX-2, and CXCL14 have already been mentioned (16)(17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 53%

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Alkasalias

Flaberg

Kashuba

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Normal human and murine fibroblasts can inhibit proliferation of tumor cells when cocultured in vitro. The inhibitory capacity varies depending on the donor and the site of origin of the fibroblast. We showed previously that effective inhibition requires formation of a morphologically intact fibroblast monolayer before seeding of the tumor cells. Here we show that inhibition is extended to motility of tumor cells and we dissect the factors responsible for these inhibitory functions. We find that inhibition is due to two different sets of molecules: (i) the extracellular matrix (ECM) and other surface proteins of the fibroblasts, which are responsible for contact-dependent inhibition of tumor cell proliferation; and (ii) soluble factors secreted by fibroblasts when confronted with tumor cells (confronted conditioned media, CCM) contribute to inhibition of tumor cell proliferation and motility. However, conditioned media (CM) obtained from fibroblasts alone (nonconfronted conditioned media, NCM) did not inhibit tumor cell proliferation and motility. In addition, quantitative PCR (Q-PCR) data show upregulation of proinflammatory genes. Moreover, comparison of CCM and NCM with an antibody array for 507 different soluble human proteins revealed differential expression of growth differentiation factor 15, dickkopf-related protein 1, endothelial-monocyteactivating polypeptide II, ectodysplasin A2, Galectin-3, chemokine (C-X-C motif) ligand 2, Nidogen1, urokinase, and matrix metalloproteinase 3.tumor microenvironment | cancer-associated fibroblast | motility | extracellular matrix | soluble factors T he normal balance between epithelial cells and the surrounding stroma is disrupted during tumor development. Developing preneoplastic cells in the process of escaping from their intrinsic checkpoints that prevent illegitimate cell proliferation also have to overcome the microenvironmental forces that maintain the integrity of the normal tissue architecture. It is becoming increasingly clear that the normal microenvironment can restrict cancer development and progression (1-3). Inhibition of tumor cell growth by normal fibroblasts is one measurable manifestation of this multicomponential control. Part of this process is reflected by the ability of the tumor cell to corrupt the surrounding stroma and turn it from restrictive to supportive. The generation of cancer-associated fibroblasts (CAFs) that enhance angiogenesis and support tumor growth and spreading through the release of growth factors and cytokines is a case in point (1-5).We have departed from the observation of Stoker et al. that normal fibroblasts can inhibit the growth of admixed tumor cells upon contact (6). Having confirmed their findings, we have extended such findings into a high throughput microwell system and showed that the strength of the inhibition differs depending on the source of the fibroblasts. Moreover, such inhibition is contact dependent as well as requires an intact fibroblast monolayer (7, 8).Here we report the surprising finding that the inhi...

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Section: Discussionmentioning

confidence: 53%

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Alkasalias

Flaberg

Kashuba

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…If the ECM of the tumour could be modified, then drug penetration into the tumour might be facilitated. Table alludes to effects of various treatment modalities on CAFs.…”

Section: Targeting Of Caf‐related Signalling Pathwaysmentioning

confidence: 99%

The role of stromal fibroblasts in lung carcinogenesis: A target for chemoprevention?

et al. 2015

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The tumour microenvironment plays an essential role in the development and spread of cancers. Tumour cells interact with the surrounding extracellular matrix (ECM), embedded within which, are a variety of non‐cancer cells including cells of the vasculature, immune system and fibroblasts. The essential role of fibroblasts in the cultivation and maintenance of an environment in which tumour cells are able to maintain their aggressive phenotypic traits is becoming increasingly well documented. Cancer‐associated fibroblasts are able to secrete a vast array of ECM‐modulating factors, meaning that they have potential for a functional role in every step of the carcinogenic process. In particular, they are likely to have a role in early tumour‐initiating inflammatory events, and so may provide a potential target for chemopreventive intervention. This review summarises the known interactions between lung tumour cells and surrounding reactive fibroblasts, highlighting the need to further investigate cancer‐associated fibroblasts as therapeutic targets in lung cancer chemoprevention strategies.

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“…Targeting PDGF receptors in the stroma has been found to inhibit lung cancer growth [280,281] and bone metastasis [282], and colon cancer growth and metastasis [283] in mouse models.…”

Section: Introductionmentioning

confidence: 99%

Targeting the PDGF signaling pathway in tumor treatment

2013

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Platelet-derived growth factor (PDGF) isoforms and PDGF receptors have important functions in the regulation of growth and survival of certain cell types during embryonal development and e.g. tissue repair in the adult. Overactivity of PDGF receptor signaling, by overexpression or mutational events, may drive tumor cell growth. In addition, pericytes of the vasculature and fibroblasts and myofibroblasts of the stroma of solid tumors express PDGF receptors, and PDGF stimulation of such cells promotes tumorigenesis. Inhibition of PDGF receptor signaling has proven to useful for the treatment of patients with certain rare tumors. Whether treatment with PDGF/PDGF receptor antagonists will be beneficial for more common malignancies is the subject for ongoing studies.

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Imatinib mesylate inhibits the proliferation-stimulating effect of human lung cancer-associated stromal fibroblasts on lung cancer cells

Cited by 22 publications

References 32 publications

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent

The role of stromal fibroblasts in lung carcinogenesis: A target for chemoprevention?

Targeting the PDGF signaling pathway in tumor treatment

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