Cancer resistance to therapy presents an ongoing and unsolved obstacle, which has clear impact on patient's survival. In order to address this problem, novel in vitro models have been established and are currently developed that enable data generation in a more physiological context. For example, extracellular-matrix- (ECM-) based scaffolds lead to the identification of integrins and integrin-associated signaling molecules as key promoters of cancer cell resistance to radio- and chemotherapy as well as modern molecular agents. In this paper, we discuss the dynamic nature of the interplay between ECM, integrins, cytoskeleton, nuclear matrix, and chromatin organization and how this affects the response of tumor cells to various kinds of cytotoxic anticancer agents. 1. Introduction Resistance to radiotherapy, chemotherapy, and novel molecular drugs still represents one of the major obstacles in cancer therapy [1–3]. Limited effectiveness of therapy inevitably results in progressive disease or recurrence, thereby reducing the chance of cure for the patients. Phenotypically, two types can be distinguished: pretherapeutically existing and acquired resistances [4, 5]. Acquired resistance to irradiation is not known, but anticancer drugs, both conventional and molecular, frequently induce defense mechanisms [6–8]. To optimize the efficacy of cytotoxic agents, it is necessary to ameliorate drug delivery to the tumor and to better understand the underlying molecular mechanisms causing the resistance or evolving the defense process [5, 9]. In order to address the latter, we and others focused on a particular cellular substructure called focal adhesion (FA) [10–17]. FAs are membrane areas, which cells employ to interact with the surrounding extracellular matrix (ECM) via integrin adhesion receptors [10, 17–22]. Due to their multiprotein composition including growth factor receptors, signaling, and adapter proteins, FAs are huge hubs for signaling downstream to control critical cell functions such as cell survival, proliferation, differentiation, and invasion [11, 13, 14, 18, 20, 22–30]. The highly complex interplay between all of these signaling molecules secures homeostasis of single cells as well as of tissues in the context of responses to external signals from the microenvironment. In tumor cells, according to the hallmarks of cancer [31], the proper physiological communication with the extracellular space is massively disturbed as a consequence of gene mutations and epigenetic modifications. Despite tumor growth-driving gene mutations, malignant cells often
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