Title:The Tumor Stroma as Mediator of Drug Resistance - A Potential Target to Improve Cancer Therapy?
Volume: 13
Issue: 11
Author(s): Susanne Sebens and Heiner Schafer
Affiliation:
Keywords:
Chemoresistance, microenvironment, apoptosis, extracellular matrix, desmoplasia, molecular targets, carcinogenesis, Drug resistance, chemotherapy, tumoral microenvironment, myofibroblasts, extracellular matrix (ECM), leukemias
Abstract: Tumors irrespective of their origin are heterogenous cellular entities whose growth and progression greatly depend
on reciprocal interactions between genetically altered (neoplastic) cells and their non-neoplastic microenvironment.
Thus, microenvironmental factors promote many steps in carcinogenesis, e.g. proliferation, invasion, angiogenesis, metastasis
and chemoresistance. Drug resistance, either intrinsic or acquired, essentially limits the efficacy of chemotherapy in
many cancer patients. To some extent, this resistance is maintained by reduced drug accumulation, alterations in drug targets
and increased repair of drug-induced DNA damage. However, the pivotal mechanism by which tumor cells elude the
cytotoxic effect of chemotherapeutic drugs is their efficient protection from induction and excecution of apoptosis. It is
meanwhile well established that cellular and non-cellular components of the tumoral microenvironment, e.g. myofibroblasts
and extracellular matrix (ECM) proteins, respectively, contribute to the anti-apoptotic protection of tumor cells.
Cellular adhesion molecules (e.g. L1CAM or CD44), chemokines (e.g. CXCL12), integrins and other ECM receptors
which are involved in direct and indirect interactions between tumor cells and their microenvironment have been identified
as suitable molecular targets to overcome chemoresistance. Accordingly, several therapeutic strategies based on these
targets have been already elaborated and tested in preclinical and clinical studies, including inhibitors and blocking antibodies
for CD44/hyaluronan, integrins, L1CAM and CXCL12. Even though these approaches turned out to be promising, the
upcoming challenge will be to prove the efficacy of these strategies in improving treatment and prognosis of cancer patients.
