Proteoglycans and neoplasia

Iozzo, Renato V.

doi:10.1007/bf00048277

Cited by 98 publications

(42 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In different types of tumours accumulation of CSPGs has been observed (Alini and Losa, 1991;Nara et al, 1991) and although the interstitial PG versican may be one of them (Nara et al, 1997), most of these tumour PGs have not been identified. Increased levels of PGs and sulphated glycosaminoglycans (sGAGs) have been described for a variety of tumours (Iozzo, 1987), including human breast tumours (Alini and Losa, 1991). Some biological functions of s-GAGs have been investigated (Jackson et al, 1991), but still most of the significance of their diversity in form and function remains unclear.…”

mentioning

confidence: 99%

Stromal accumulation of chondroitin sulphate in mammary tumours of dogs

1999

View full text Add to dashboard Cite

To contribute to the investigation of the composition of the extracellular matrix in epithelial tumours, mammary gland tissues of dogs (including tumours, hyperplasias and normal tissue as well as metastatic lesions in lymph nodes and lung) were studied histochemically and immunohistochemically for distribution of sulphated glycosaminoglycans (s-GAGs). The formaline-fixed tissue was stained by alcian blue at pH 5.8, using the ‘critical electrolyte concentration’ to study the degree of sulphation of s-GAGs. s-GAGs were characterized by degradation with enzymes and nitrous acid and by immunohistochemistry with two anti-chondroitin sulphate monoclonal antibodies. The light microscopic investigation of s-GAG deposits revealed a limited number of patterns of their distribution. The main s-GAGs found in the mammary gland tumours of dogs and in metastatic lesions were chondroitin sulphate (CS) and heparin/heparan sulphate (HEP/HS). CS accumulated in diffuse structures between epithelial cells as well as around clusters of tumour cells. The latter pattern, possibly representing a mesenchymal reaction to the tumour, was present in 74% of the tumours, and in 67% of these, highly sulphated CS was present. A diffuse accumulation of CS was present almost exclusively in complex and mixed tumours; because of the expression of the 3B3 epitope for CS in immature cartilage the spindle cells of complex tumours are argued to be the precursors of the cartilage in mixed tumours. HEP/HS was stored mainly in mast cells that were found in increased numbers in hyperplasias and tumours. By pretreatment of microscopic slides with chondroitinase AC or ABC immunostaining of fibronectin could be made possible in areas in which CS was abundantly present, suggesting that CS may mask fibronectin epitopes. It is concluded that CS with different degrees of sulphation is the most important s-GAG in the extracellular matrix of mammary tumours of dogs. CS and other s-GAGs accumulate at different sites and may have a different pathogenetic significance. © 1999 Cancer Research Campaign

show abstract

mentioning

confidence: 99%

Stromal accumulation of chondroitin sulphate in mammary tumours of dogs

1999

View full text Add to dashboard Cite

show abstract

“…The ECM constituents in tumours are normally produced by the stromal cells of the host, whereas the tumour cells may modulate the synthesis rate to ensure a favourable environment for the Experimental Therapeutics Diffusion and extracellular matrix C de L Davies et al malignant cells (Iozzo, 1988 , 1997). Consistent with this, we also found less collagen and GAG in the spheroids compared to the tumours.…”

Section: Indirect Influence Of Stromal Cells On the Transport Parametersmentioning

confidence: 99%

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

et al. 2002

View full text Add to dashboard Cite

The tumour extracellular matrix acts as a barrier to the delivery of therapeutic agents. To test the hypothesis that extracellular matrix composition governs the penetration rate of macromolecules in tumour tissue, we measured the diffusion coefficient of nonspecific IgG in three rhabdomyosarcoma subclones growing as multicellular spheroids in vitro or as subcutaneous tumours in dorsal windows in vivo. In subcutaneous tumours, the diffusion coefficient decreased with increasing content of collagen and sulphated glycosaminoglycans. When grown as multicellular spheroids, no differences in either extracellular matrix composition or diffusion coefficient were found. Comparison of in vitro vs in vivo results suggests an over-riding role of host stromal cells in extracellular matrix production subjected to modulation by tumour cells. Penetration of therapeutic macromolecules through tumour extracellular matrix might thus be largely determined by the host organ. Hence, caution must be exercised in extrapolating drug penetrability from spheroids and multilayer cellular sandwiches consisting of only tumour cells to tumours in vivo. British Journal of Cancer (2002) The extracellular matrix (ECM) is a potent barrier to the delivery and penetration of complex biopharmaceuticals such as monoclonal antibodies, therapeutic proteins, or genes. Due to the elevated interstitial fluid pressure in tumours , the therapeutic agents must reach the tumour cells by interstitial diffusion. It is not clear whether the network of fibrillar collage or the glycosaminoglycan (GAG) gel plays the most important role in limiting the diffusion of macromolecules through the ECM, and what the role of the host stromal cells is. Netti et al (2000) found that the amount of collagen in tumours correlated inversely with the diffusion coefficient of macromolecules, and collagenase treatment of the tumour increased the diffusion coefficient. Pluen et al (2001) provided further support for the role of collagen by measuring diffusion in tumours grown in subcutaneous tissue and the cranium. Hyaluronidase, on the other hand, is reported to reduce the diffusion coefficient of albumin in lung interstitium (Qiu et al, 1999).We postulated that diffusion of macromolecules is hindered both by the collagen network and by the hydrophilic gel of GAG and proteoglycans. To test this hypothesis we used three distinct clones with different degrees of differentiation and ECM (Groeschel et al, 1994) derived from a rat rhabdomyosarcoma, growing as multicellular spheroids in vitro or subcutaneously in dorsal chambers in mice in vivo. The production of ECM in tumours is the result of an active interaction between the tumour cells and stromal cells of the host (Gullino and Grantham, 1962;Knudson et al, 1984), whereas the extracellular matrix of multicellular spheroids is solely produced by the tumour cells. Comparison of the ECM composition in tumours growing as xenografts in vivo and as multicellular spheroids in vitro, is likely to reveal the influence of the host stromal ce...

show abstract

“…There has been a long standing association between alterations in both the levels of production and the overall sulfation of HS and the development of malignant mammary tumors (14,15). In cellular models of breast cancer, analogous changes in the gross structure of HS have been observed, whereas changes in the levels of expression of the core protein of the HS proteoglycan syndecan-1 may be causally related to the acquisition of a malignant phenotype by mammary tumor cells in vitro (16 -18).…”

mentioning

confidence: 99%