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Review
. 2008 Jan;57(1):1-17.
doi: 10.1007/s00262-007-0365-5. Epub 2007 Jul 27.

Anti-cancer therapies targeting the tumor stroma

Valeska Hofmeister  1 , David Schrama, Jürgen C Becker
Affiliations
Review

"V体育官网入口" Anti-cancer therapies targeting the tumor stroma

"VSports最新版本" Valeska Hofmeister et al. Cancer Immunol Immunother. 2008 Jan.

Abstract

For anti-tumor therapy different strategies have been employed, e. g. , radiotherapy, chemotherapy, or immunotherapy. Notably, these approaches do not only address the tumor cells themselves, but also the tumor stroma cells, e. g. , endothelial cells, fibroblasts, and macrophages. This is of advantage, since these cells actively contribute to the proliferative and invasive behavior of the tumor cells via secretion of growth factors, angiogenic factors, cytokines, and proteolytic enzymes. In addition, tumor stroma cells take part in immune evasion mechanisms of cancer. Thus, approaches targeting the tumor stroma attract increasing attention as anti-cancer therapy. Several molecules including growth factors (e. g. , VEGF, CTGF), growth factor receptors (CD105, VEGFRs), adhesion molecules (alphavbeta3 integrin), and enzymes (CAIX, FAPalpha, MMPs, PSMA, uPA) are induced or upregulated in the tumor microenvironment which are otherwise characterized by a restricted expression pattern in differentiated tissues VSports手机版. Consequently, these molecules can be targeted by inhibitors as well as by active and passive immunotherapy to treat cancer. Here we discuss the results of these approaches tested in preclinical models and clinical trials. .

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"VSports在线直播" Figures

Fig. 1
Fig. 1
Influence of the tumor microenvironment on tumor development. Tumor stromal cells, e.g., cancer associated fibroblasts (CAFs), tumor endothelial cells (TECs), and tumor-associated macrophages (TAMs) express growth factors sustaining tumor growth, angiogenic factors promoting angiogenesis, and proteolytic enzymes catalyzing the degradation of the ECM facilitating tumor cell invasion and finally metastasis. Tumor cells are depicted in brown, CAFs in orange, TECs in red, and TAMs in yellow
Fig. 2
Fig. 2
Targeting endothelial cells for anti cancer therapy. A variety of proteins are targeted to prevent angiogenesis. a The function of molecules expressed on endothelial cells, e.g., VEGFRs, PSMA, TEM8, and CD105 is inhibited either directly by inhibitors and antibodies or alternatively their expression is prevented by ribozymes. In addition, they are exploited to eliminate tumor endothelial cells, e.g., by bispecific antibodies or specific expression or accumulation of toxins at endothelial cells. b CTGF is targeted by siRNA, inhibitors or antibodies. αvβ3 integrin expression is prevented by siRNA, its function is inhibited by antibodies, and effector molecules are targeted to αvβ3 integrin positive cells using inhibitors binding to αvβ3 integrin. Expression/secretion of target molecules is indicated by green arrows, binding to receptors by brown arrows, and their effects by black arrows. Therapeutical substances are depicted in red and their effects by blue arrows
Fig. 3
Fig. 3
Therapy approaches influencing the ECM degradation and targeting CAFs. a MMPs and the uPA/uPAR system influence the ECM degradation in the tumor microenvironment and promote invasion and metastasis of tumors. They are targeted by inhibiting their expression, e.g., by siRNA, antisense constructs, ribozymes or DNAzymes or their function by inhibitors, antibodies or soluble receptors, for example. In addition the uPA/uPAR system is used to induce apoptosis by recruitment or activation of toxins. b Tenascin expression is downregulated by siRNA approaches or targeted by antibodies or aptamers labeled with radioisotopes. Molecules expressed on the cell surface of CAFs, e.g., c FAPα and d CAIX, are also used to directly destroy these stroma cells mediated by antibodies (labeled with radioactive isotopes or different effector molecules) or cellular immune responses. Expression/secretion of target molecules is indicated by green arrows, binding to receptors by brown arrows, and their effects by black arrows. Therapeutical substances are depicted in red and their effects by blue arrows
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