Elsevier

Differentiation

Volume 70, Issues 9–10, December 2002, Pages 486-497
Differentiation

REVIEW
Tumor-stroma interactions directing phenotype and progression of epithelial skin tumor cells

https://doi.org/10.1046/j.1432-0436.2002.700903.xGet rights and content

Abstract

Tumor-stroma interactions play a significant role in tumor development and progression. Alterations in the stromal microenvironment, including enhanced vasculature (angiogenesis), modified extracellular matrix composition, inflammatory cells, and dys-balanced protease activity, are essential regulatory factors of tumor growth and invasion. Differential modulation of stromal characteristics is induced by epithelial skin tumor cells depending on their transformation stage when grown as surface transplants in vivo. Tumor cells can regulate the development of a “tumor-stroma” via the aberrant expression of growth factors or induction of growth factor receptors in the stromal compartment. In this context, secretion of the hematopoietic growth factors G-CSF and GM-CSF, constituitively expressed in enhanced malignant tumors, may be good candidates for induction of a tumor stroma through their effect on inflammatory cells. Upon its induction, the tumor stroma will reciprocally influence the differentiation status of tumor cells resulting in a normalization of benign tumor epithelia and the maintenance of a malignant phenotype, respectively. In the HaCaT model for squamous cell carcinoma of the skin, stromal activation and angiogenesis are transient in pre-malignant transplants, however they remain persistent in malignant transplants where progressive angiogenesis is closely correlated with tumor invasion. While continued expression of VEGF and PDGF are associated with benign tumor phenotypes, activation of VEGFR-2 is a hallmark of malignant tumors and accompanies ongoing angiogenesis and tumor invasion. As a consequence the inhibition of ongoing angiogenesis by blocking VEGFR-2 signalling resulted in dramatically impaired malignant tumor expansion and invasion. Comparably, tumor vascularization and invasion was blocked by disturbing the balance of matrix protease activity caused by a lack of PAI-1 in the stromal cells of the knockout mouse hosts. A similar inhibition of tumor vascularization was caused by TSP-1 over-expression in skin carcinoma cells, which also blocked tumor invasion and expansion. On the other hand, when granulation tissue and angiogenesis were only transiently activated as a result of stable transfection of PDGF into non-tumorigenic HaCaT cells, the target cells formed benign, but not malignant, tumors. Collectively, these data show that tumor vascularization, providing intimate association of blood vessels with tumor cells, is a prerequisite for tumor invasion. A potential mechanism for this interrelationship may be the differential regulation of MMP-expression in tumors of different grades of malignancy. In vitro MMP expression did not discriminate between benign and malignant tumor cells unless they were co-cultured with stromal fibroblasts. However, in vivo regulation of MMP expression was clearly dependent on tumor phenotype. While MMP-1 and MMP-13 were down-regulated in benign transplants, they were persistently up-regulated in malignant ones. A tight balance between proteases and their inhibitors is crucial for both the formation and infiltration of blood vessels and for tumor cell invasion, thus again emphasizing the importance of the stromal compartment for the development and progression of carcinomas.

References (69)

  • C.M. Ryle et al.

    Density-dependent modulation of synthesis of keratins l and 10 in the human keratinocyte line HaCaT and in ras-transfected tumorigenic clones

    Differentiation

    (1989)
  • V. Schoop et al.

    Epidermal organization and differentiation of HaCaT keratinocytes in organotypic coculture with human dermal fibroblasts

    J Invest Dermatol

    (1999)
  • T.D. Tlsty

    Stromal cells can contribute to oncogenic signals. Semin

    Cancer Biol

    (2001)
  • P. Tomakidi et al.

    Defects of basement membrane and hemidesmosome structure correlate with malignant phenotype and stromal interactions in HaCaT-ras xenografts

    Differentiation

    (1999)
  • M.A. Turner et al.

    Epithelial-stromal interactions modulating penetration of matrigel membranes by HPV 16-immortalized keratinocytes

    J Invest Dermatol

    (1997)
  • J. Yuan et al.

    Mutagenesis induced by the tumor microenvironment

    Mutat Res

    (1998)
  • B.E. Bachmeier et al.

    Matrix metalloproteinases-2,-3,-7,-9 and-10, but not MMP-11, are differentially expressed in normal, benign tumorigenic and malignant human keratinocyte cell lines

    Biol Chem

    (2000)
  • K. Bajou et al.

    The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin: implications for anti-angiogenic strategies

    J Cell Biol

    (2001)
  • K. Bajou et al.

    Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization

    Nature Medicine

    (1998)
  • R. Billingham et al.

    Transplantation of skin components during chemical carcinogenesis with 20-methylcholanthrene

    Br J Cancer

    (1951)
  • K. Bleuel et al.

    Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization

    Proc Natl Acad Sci USA

    (1999)
  • A.H. Borchers et al.

    Fibroblast-Directed Expression and Localization of 92-kDa Type IV Collagenase Along the Tumor-Stroma Interface in an in Vitro Three-Dimensional Model of Human Squamous Cell Carcinoma

    Molecular Carcinogenesis

    (1997)
  • P. Borgstrom et al.

    Complete inhibition of angiogenesis and growth of micro-tumours by anti-vascular endothelial growth factor neutralizing antibody: novel concepts of angiostatic therapy from intravital videomicroscopy

    Cancer Res

    (1996)
  • P. Boukamp et al.

    Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line

    J Cell Biol

    (1988)
  • P. Boukamp et al.

    Sustained nontumorigenic phenotype correlates with a largely stable chromosome content during long-term culture of the human keratinocyte line HaCaT

    Genes, Chromsomes & Cancer

    (1997)
  • P. Boukamp et al.

    c-Ha-ras oncogene expression in immortalized human keratinocytes (HaCaT) alters growth potential in vivo but lacks correlation with malignancy

    Cancer Res

    (1990)
  • M. Brauchle et al.

    Large induction of keratinocyte growth factor expression by serum growth factors and pro-inflammatory cytokines in cultured fibroblasts

    Oncogene

    (1994)
  • D. Breitkreutz et al.

    Epidermal morphogenesis and keratin expression in c-Ha-ras-transfected tumorigenic clones of the human HaCaT cell line

    Cancer Res

    (1991)
  • C. Chang et al.

    The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis

    Trends Cell Biol

    (2001)
  • L.W. Chung

    The role of stromal-epithelial interaction in normal and malignant growth

    Cancer Surv

    (1995)
  • J. Cornil et al.

    Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression

    Proc Natl Acad Sci USA

    (1991)
  • L. Coussens et al.

    Inflammatory cells and cancer

    J Exp Med

    (2001)
  • K.P. Dingemans et al.

    Transplantation of colon carcinoma into granulation tissue induces an invasive morphotype

    Int J Cancer

    (1993)
  • H.F. Dvorak

    Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing

    New Engl Med

    (1986)
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