Tumor Stroma Formation in Lung Cancer

Vignaud, Jean-Michel; Marie, Béatrice; Picard, E; Nabil, Karim Mahmoud; Siat, Joëlle; Galateau-Sallé, Françoise; Borrelly, J; Martinet, Yves; Martinet, Nadine

doi:10.1007/978-3-0348-8924-7_7

Cited by 6 publications

(6 citation statements)

References 73 publications

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“…In epithelial tumors, this appositional expression of PDGF-BB and its receptor has been documented in basal cell carcinoma of the skin (12), but also in breast (28), lung (29), and colorectal cancer (30). Here we report that human keratinocytes transfected with PDGF-B induce a highly proliferative and well-vascularized stroma after s.c. injection into nude mice.…”

Section: Discussionmentioning

confidence: 52%

Tumorigenic conversion of immortal human keratinocytes through stromal cell activation

Skobe

Fusenig

1998

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

203

135

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The stromal microenvironment plays a crucial role in tumor development and progression. One of the most potent activators of stromal cells is the platelet-derived growth factor (PDGF). To investigate the role of PDGF in epithelial tumor development we stably transfected immortal nontumorigenic human keratinocytes with the PDGF-B cDNA. Transfected HaCaT cells overexpressed PDGF-B but remained negative for the PDGF receptors ␣ and ␤ (mRNA). Thus, they did not exhibit autocrine growth stimulation in vitro, but proliferation of cocultured fibroblasts was enhanced and this effect was inhibited by a neutralizing antibody to PDGF-BB. After subcutaneous injection into nude mice the transfected cells maintained high PDGF expression and formed progressively enlarging, rapidly proliferating cysts, classified as benign tumors. During early tumor development (up to 2 months), PDGF-B transfectants induced marked mesenchymal cell proliferation and angiogenesis, yet this effect vanished at later stages (2-6 months) concomitantly with increased epithelial cell proliferation and enhanced tumor growth. These results demonstrate that an activated stromal environment can promote tumorigenic conversion of nontumorigenic keratinocytes by inducing sustained epithelial hyperproliferation. This effect is apparently caused by a dual action of PDGF-BB: (i) PDGF-BB can promote tumor growth by inducing angiogenesis and stroma formation, and (ii) PDGF-activated stromal cells maintain elevated keratinocyte proliferation via a paracrine mechanism. Thus, PDGF, a major factor activated in wound healing, may play an important role as an endogenous promoter in epithelial tumor formation.

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Section: Discussionmentioning

confidence: 52%

Tumorigenic conversion of immortal human keratinocytes through stromal cell activation

Skobe

Fusenig

1998

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

203

135

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“…Although PDGF plays a critical role in wound healing and developmental processes (Ataliotis and Mercola, 1997), accumulating evidence suggests that its abnormal expression contributes to a variety of diseases including cancer (Aaronson, 1991;Betsholtz and Raines, 1997;Dirks and Bloemers, 1996;Heldin and Westermark, 1991). The role of PDGF in glioma (Fleming et al, 1992), ®brosarcoma (Fleming et al, 1992), mesothelioma (Van der Meeren et al, 1993) and lung cancer (Vignaud et al, 1994) has been clearly documented. Among the PDGF isoforms, PDGF BB is the human homolog of the v-sis oncogene product Doolittle et al, 1983;Water®eld et al, 1983).…”

Section: Introductionmentioning

confidence: 99%

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

et al. 1999

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“…A combination of autocrine and paracrine loops involving PDGF ligands and receptors was demonstrated in human glioblastomas (Hermanson et al, 1992) and AIDS-related Kaposi's sarcoma (Sturzl et al, 1992). PDGF appears to have a paracrine e ect on tumor stroma development in basal cell carcinoma (Ponten et al, 1994) and lung cancer (Vignaud et al, 1994). Smits et al (1992) demonstrated that, while PDGFb receptors are expressed in various proliferative disorders, PDGFa receptors are expressed only on fully malignant disorders of ®broblastic origin.…”

Section: Discussionmentioning

confidence: 99%

Modification of PDGFα receptor expression or function alters the metastatic phenotype of 3LL cells

Fitzer‐Attas

Feigelson

et al. 1997

Oncogene

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Functional PDGFa receptors are selectively expressed on highly lung-metastasizing clones of the 3LL Lewis lung carcinoma, but not on low-mestastatic clones. The highly metastatic clones are also growth induced in vitro by PDGF and lung conditioned medium. To investigate whether modi®cation of PDGFa receptor expression or function can a ect metastatic capability, we transfected cells of a low-metastatic 3LL clone with a full length PDGFa receptor gene and cells of a highly-metastatic clone with a truncated kinase domain PDGFa receptor gene. Introduction of the full length PDGFa receptor conferred upon low-metastatic cells the ability to grow in vitro in the presence of PDGF-AA and to colonize the lung in experimental and spontaneous metastases assays. Conversely, introduction of a truncated version of the PDGFa receptor into highly metastatic cells reduced their metastatic load to control levels. Accordingly, their responses to PDGF-AA, including growth stimulation and receptor autophosphorylation, were reduced. These results demonstrate that PDGFa receptor expression and function can control the capacity of tumor cells to generate metastases in the lung. The response of this receptor to lung-derived PDGF-like factors may de®ne a paracrine mode of metastatic cell growth in the target organ.

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Tumor Stroma Formation in Lung Cancer

Cited by 6 publications

References 73 publications

Tumorigenic conversion of immortal human keratinocytes through stromal cell activation

Tumorigenic conversion of immortal human keratinocytes through stromal cell activation

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

Modification of PDGFα receptor expression or function alters the metastatic phenotype of 3LL cells

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