The tumor microenvironment: a critical determinant of neoplastic evolution

doi:10.1078/0171-9335-00346

European Journal of Cell Biology

Volume 82, Issue 11, November 2003, Pages 539-548

https://doi.org/10.1078/0171-9335-00346 Get rights and content

Summary

Evolution of neoplastic cells has generally been regarded as a cumulative intrinsic process resulting in altered cell characteristics enabling enhanced growth properties, evasion of apoptotic signals, unlimited replicative potential and gain of properties enabling the ability to thrive in ectopic tissues and in some cases, ability to metastasize. Recently however, the role of the neoplastic microenvironment has become appreciated largely due to the realization that tumors are not merely masses of neoplastic cells, but instead, are complex tissues composed of both a non-cellular (matrix proteins) and a cellular ‘diploid' component (tumor-associated fibroblasts, capillary-associated cells and inflammatory cells), in addition to the ever-evolving neoplastic cells. With these realizations, it has become evident that early and persistent inflammatory responses observed in or around many solid tumors, play important roles in establishing an environment suitable for neoplastic progression by providing diverse factors that alter tissue homeostasis. Using cutaneous melanoma and squamous cell carcinoma as tumor models, we review the current literature focussing on inflammatory and tumor-associated fibroblast responses as critical mediators of neoplastic progression for these malignancies.

References (105)

K. Airola et al.
Human collagenase-3 is expressed in malignant squamous epithelium of the skin
J. Invest. Dermatol.
(1997)
F. Balkwill et al.
Inflammation and cancer: back to Virchow?
Lancet
(2001)
G. Bergers et al.
Extrinsic regulators of epithelial tumor progression: metalloproteinases
Curr. Opin. Genet. Dev.
(2000)
L.M. Coussens et al.
MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis
Cell
(2000)
G.A. Di Lullo et al.
Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen
J. Biol. Chem.
(2002)
A.M. Dvorak et al.
Melanoma. An ultrastructural study of the host inflammatory and vascular responses
J. Invest. Dermatol.
(1980)
K.C. Fang et al.
Dog mast cell alpha-chymase activates progelatinase B by cleaving the Phe88-Gln89 and Phe91-Glu92 bonds of the catalytic domain
J. Biol. Chem.
(1997)
E.R. Fearon et al.
A genetic model for colorectal tumourigenesis
Cell
(1990)
A.K. Ghosh et al.
Antagonistic regulation of type I collagen gene expression by interferon-γ and transforming growth factor-β. Integration at the level of p300/CBP transcriptional coactivators
J. Biol. Chem
(2001)
T.A. Giambernardi et al.
Neutrophil collagenase (MMP-8) is expressed during early development in neural crest cells as well as in adult melanoma cells
Matrix Biol.
(2001)

E. Gustafsson et al.

Insights into extracellular matrix functions from mutant mouse models

Exp. Cell Res.

(2000)

Y. Hamano et al.

Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaVbeta3 integrin

Cancer Cell

(2003)

D. Hanahan et al.

The hallmarks of cancer

Cell

(2000)

H. Hashizume et al.

Openings between defective endothelial cells explain tumor vessel leakiness

Am. J. Pathol.

(2000)

K.A. Hasty et al.

Human neutrophil collagenase. A distinct gene product with homology to other matrix metalloproteinases

J. Biol. Chem.

(1990)

U.B. Hofmann et al.

Matrix metalloproteinases in human melanoma

J. Invest. Dermatol.

(2000)

M.-Y. Hsu et al.

Melanoma development and progression: a conspiracy between tumor and host

Differentiation

(2002)

Y. Inagaki et al.

Interferon alfa down-regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice

Hepatology

(2003)

C.J. Jackson et al.

Type I collagen fibrils promote rapid vascular tube formation upon contact with the apical side of cultured endothelium

Exp. Cell Res.

(1991)

E. Kerkela et al.

Expression of human macrophage metalloelastase (MMP-12) by tumor cells in skin cancer

J. Invest. Dermatol.

(2000)

C.C. Lynch et al.

Matrix metalloproteinases in tumor-host cell communication

Differentiation

(2002)

A. Mantovani et al.

Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes

Trends Immunol.

(2002)

G. Oxford et al.

Ras superfamily monomeric G proteins in carcinoma cell motility

Cancer Lett.

(2003)

D. Ruiter et al.

Melanomastroma interactions: structural and functional aspects

Lancet Oncol.

(2002)

S.F. Schoppmann et al.

Tumorassociated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis

Am. J. Pathol.

(2002)

M. Seandel et al.

Growth factor-induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen

Blood

(2001)

S.D. Shapiro et al.

Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages

J. Biol. Chem.

(1993)

A. Sica et al.

Tumor-associated macrophages: a molecular perspective

Int. Immunopharmacol.

(2002)

M. Skobe et al.

Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma

Am. J. Pathol.

(2001)

G. Spira et al.

Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats

J. Hepatol.

(2002)

I. Stamenkovic

Matrix metalloproteinases in tumor invasion and metastasis

Semin. Cancer Biol.

(2000)

D. Tuckwell

Identification and analysis of collagen alpha 1(XXI), a novel member of the FACIT collagen family

Matrix Biol.

(2002)

J. Uitto et al.

Cytokine modulation of extracellular matrix gene expression: relevance to fibrotic skin diseases

J. Dermatol. Sci

(2000)

L.C. Van Kempen et al.

Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment

Differentiation

(2002)

D.A. Vesey et al.

Interleukin-1beta stimulates human renal fibroblast proliferation and matrix protein production by means of a transforming growth factor-beta-dependent mechanism

J. Lab. Clin. Med.

(2002)

M. Abe et al.

Mast cell tryptase stimulates both human dermal fibroblast proliferation and type I collagen production

Clin. Exp. Allergy

(1998)

K. Airola et al.

Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas

Br. J. Cancer

(1999)

A. Balmain et al.

The genetics and genomics of cancer

Nat. Genet

(2003)

G. Bergers et al.

Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

Nat. Cell Biol.

(2000)

C. Berking et al.

Transforming growth factor-beta1 increases survival of human melanoma through stroma remodeling

Cancer Res.

(2001)

A. Berndt et al.

Fibrillary codeposition of laminin-5 and large unspliced tenascin-C in the invasive front of oral squamous cell carcinoma in vivo and in vitro

J. Cancer Res. Clin. Oncol.

(2001)

L. Bingle et al.

The role of tumourassociated macrophages in tumour progression: implications for new anticancer therapies

J. Pathol.

(2002)

W. Birchmeier

E-cadherin as a tumor (invasion) suppressor gene

Bioessays

(1995)

M.J. Bissell et al.

Putting tumours in context

Nat. Rev. Cancer

(2001)

F. Blasi et al.

uPAR: a versatile signalling orchestrator

Nat. Rev. Mol. Cell Biol.

(2002)

D. Bodmer et al.

Understanding familial and non-familial renal cell cancer Hum

Mol. Genet.

(2002)

B. Bodey et al.

Matrix metalloproteinase expression in malignant melanomas: tumor-extracellular matrix interactions in invasion and metastasis

In Vivo

(2001)

E.B. Brocker et al.

Infiltration of primary and metastatic melanomas with macrophages of the 25F9-positive phenotype

Cancer Immunol. Immunother.

(1987)

J.A. Cairns et al.

Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts

J. Clin. Invest.

(1997)

P. Carmeliet

Angiogenesis in health and disease

Nat. Med.

(2003)

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The tumor microenvironment: a critical determinant of neoplastic evolution

Summary

J. Invest. Dermatol.

Lancet

Curr. Opin. Genet. Dev.

Cell

J. Biol. Chem.

J. Invest. Dermatol.

J. Biol. Chem.

Cell

J. Biol. Chem

Matrix Biol.

Exp. Cell Res.

Cancer Cell

Cell

Am. J. Pathol.

J. Biol. Chem.

J. Invest. Dermatol.

Differentiation

Hepatology

Exp. Cell Res.

J. Invest. Dermatol.

Differentiation

Trends Immunol.

Cancer Lett.

Lancet Oncol.

Am. J. Pathol.

Blood

J. Biol. Chem.

Int. Immunopharmacol.

Am. J. Pathol.

J. Hepatol.

Semin. Cancer Biol.

Matrix Biol.

J. Dermatol. Sci

Differentiation

J. Lab. Clin. Med.

Mast cell tryptase stimulates both human dermal fibroblast proliferation and type I collagen production

Clin. Exp. Allergy

Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas

Br. J. Cancer

The genetics and genomics of cancer

Nat. Genet

Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis

Nat. Cell Biol.

Transforming growth factor-beta1 increases survival of human melanoma through stroma remodeling

Cancer Res.

Fibrillary codeposition of laminin-5 and large unspliced tenascin-C in the invasive front of oral squamous cell carcinoma in vivo and in vitro

J. Cancer Res. Clin. Oncol.

The role of tumourassociated macrophages in tumour progression: implications for new anticancer therapies

J. Pathol.

E-cadherin as a tumor (invasion) suppressor gene

Bioessays

Putting tumours in context

Nat. Rev. Cancer

uPAR: a versatile signalling orchestrator

Nat. Rev. Mol. Cell Biol.

Understanding familial and non-familial renal cell cancer Hum

Mol. Genet.

Matrix metalloproteinase expression in malignant melanomas: tumor-extracellular matrix interactions in invasion and metastasis

In Vivo

Infiltration of primary and metastatic melanomas with macrophages of the 25F9-positive phenotype

Cancer Immunol. Immunother.

Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts

J. Clin. Invest.

Angiogenesis in health and disease

Nat. Med.