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Background: Focal adhesion signaling involving receptor tyrosine kinases (RTK) and integrins co-controls cancer cell survival and therapy resistance. However, co-dependencies between these receptors and therapeutically exploitable vulnerabilities remain largely elusive in HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods: The cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin was determined in up to 20 3D matrix-grown HNSCC cell models followed by drug screening and patient-derived organoid validation. RNA sequencing and protein-based biochemical assays were performed for molecular characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. Results: Fibroblast growth factor receptor (FGFR 1–4) targeting exhibited the strongest cytotoxic and radiosensitizing effects as monotherapy and combined with β1 integrin inhibition, exceeding the efficacy of the other RTK studied. Pharmacological pan-FGFR inhibition elicited responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence analysis revealed a mesenchymal-to-epithelial transition (MET) in sensitive cell models, whereas resistant cell models exhibited a partial epithelial-to-mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid-dependently. Transferring the EMT-associated transcriptomic profiles to HNSCC patient cohorts not only demonstrated their prognostic value but also provided a conclusive validation of the presence of EGFR-related vulnerabilities that can be strategically exploited for therapeutic interventions. Conclusions: This study demonstrates that pan-FGFR inhibition elicits a beneficial radiochemosensitizing and a detrimental radioprotective potential in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically. [ABSTRACT FROM AUTHOR]

Constitutively active kinases play a crucial role in carcinogenesis, and their inhibition is a common target for molecular tumor therapy. We recently discovered the expression of two oncogenic isoforms of Bruton's Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC), Btk-p80 and BTK-p65. However, the precise role of BTK in HNSCC remains unclear. Analyses of a tissue microarray containing benign and malignant as well as inflammatory tissue samples of the head and neck region revealed the preferential expression of BTK-p80 in malignant tissue, whereas BTK-p65 expression was confirmed in over 80% of analyzed metastatic head and neck tumor cases. Therefore, processes associated with metastasis, like cancer stem cell (CSC) enrichment and the epithelial–mesenchymal transition (EMT), which in turn depend on an appropriate cytokine milieu, were analyzed. Treatment of HNSCC-derived cell lines cultured under 3D conditions with the BTK inhibitor AVL-292 caused reduced sphere formation, which was accompanied by reduced numbers of ALDH1A1+ CSCs as well as biological changes associated with the EMT. Moreover, we observed reduced NF-κB expression as well as altered NF-κB dependent pro-tumorigenic and EMT-associated cytokine release of IL-6, IFNγ, and TNFα when BTK activity was dampened. Therefore, an autocrine regulation of the oncogenic BTK-dependent process in HNSCC can be suggested, with BTK inhibition expected to be an effective treatment option for HNSCC. [ABSTRACT FROM AUTHOR]

BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1. [ABSTRACT FROM AUTHOR]

The relative configuration of the marine sesquiterpenoid oxyfungiformin, isolated from the soft coral Capnella fungiformis, was confirmed by synthesis using the natural product guaiol as chiral precursor. The absolute configuration of oxyfungiformin could be assigned by combination of X‐ray diffraction and comparison of the values for the specific optical rotation. Oxyfungiformin and a diastereoisomer showed cytotoxic activity in cells originating from cancers of the lung, breast, and cervix. [ABSTRACT FROM AUTHOR]

Glioblastoma is a devastating malignant disease with poor patient overall survival. Strong invasiveness and resistance to radiochemotherapy have challenged the identification of molecular targets that can finally improve treatment outcomes. This study evaluates the influence of all six known p21-activated kinase (PAK) protein family members on the invasion capacity and radio-response of glioblastoma cells by employing a siRNA-based screen. In a panel of human glioblastoma cell models, we identified PAK4 as the main PAK isoform regulating invasion and clonogenic survival upon irradiation and demonstrated the radiosensitizing potential of PAK4 inhibition. Mechanistically, we show that PAK4 depletion and pharmacological inhibition enhanced the number of irradiation-induced DNA double-strand breaks and reduced the expression levels of various DNA repair proteins. In conclusion, our data suggest PAK4 as a putative target for radiosensitization and impairing DNA repair in glioblastoma, deserving further scrutiny in extended combinatorial treatment testing. [ABSTRACT FROM AUTHOR]

Cell adhesion to extracellular matrix proteins mediates resistance to radio- and chemotherapy by activating integrin signaling. In addition, mutual and cooperative interactions between integrin and growth factor receptor signaling contribute to the cellular radiation response. Here, we investigate to which extend the crosstalk between β1 integrins and growth factor receptor signaling determines the cellular radiation response of fibroblasts by assessing clonogenic survival and cell cycling. By utilizing growth factor signaling competent and either β1 integrin wildtype GD25β1A fibroblasts or β1 integrin mutant, signaling incompetent GD25β1B fibroblasts, we show basal clonogenic survival to depend on growth factor receptor but not integrin signaling. Our data further suggest the cooperation between β1 integrins and growth factor receptors to be critical for enhancing the radiation-induced G2/M cell cycle block leading to improved clonogenic radiation survival. By pharmacological inhibition of EGFR and PI3K, we additionally show that the essential contribution of EGFR signaling to radiogenic G2/M cell cycle arrest depends on the co-activation of the β1 integrin signaling axis, but occurs independent of PI3K. Taken together, elucidation of the signaling circuitry underlying the EGFR/β1 integrin crosstalk may support the development of advanced molecular targeted therapies for radiation oncology. [ABSTRACT FROM AUTHOR]

Purpose: The current status of German residency training in the field of radiation oncology is provided and compared to programmes in other countries. In particular, we present the DEGRO-Academy within the international context.Methods: Certified courses from 2018 and 2019 were systematically assigned to the DEGRO-Curriculum, retrospectively for 2018 and prospectively for 2019. In addition, questionnaires of course evaluations were provided, answered by course participants and collected centrally.Results: Our data reveal a clear increase in curriculum coverage by certified courses from 57.6% in 2018 to 77.5% in 2019. The analyses enable potential improvements in German curriculum-based education. Specific topics of the DEGRO-Curriculum are still underrepresented, while others decreased in representation between 2018 and 2019. It was found that several topics in the DEGRO-Curriculum require more attention because of a low DEGRO-curriculum coverage. Evaluation results of certified courses improved significantly with a median grade of 1.62 in 2018 to 1.47 in 2019 (p = 0.0319).Conclusion: The increase of curriculum coverage and the simultaneous improvement of course evaluations are promising with respect to educational standards in Germany. Additionally, the early integration of radiation oncology into medical education is a prerequisite for resident training because of rising demands on quality control and increasing patient numbers. This intensified focus is a requirement for continued high standards and quality of curriculum-based education in radiation oncology both in Germany and other countries. [ABSTRACT FROM AUTHOR]

Alterations in mechano-physiological properties of a tissue instigate cancer burdens in parallel to common genetic and epigenetic alterations. The chronological and mechanistic interrelation between the various extra- and intracellular aspects remains largely elusive. Mechano-physiologically, integrins and other cell adhesion molecules present the main mediators for transferring and distributing forces between cells and the extracellular matrix (ECM). These cues are channeled via focal adhesion proteins, termed the focal adhesomes, to cytoskeleton and nucleus and vice versa thereby affecting the pathophysiology of multicellular cancer tissues. In combination with simultaneous activation of diverse downstream signaling pathways, the phenotypes of cancer cells are created and driven characterized by deregulated transcriptional and biochemical cues that elicit the hallmarks of cancer. It, however, remains unclear how elastostatic modifications, i.e., stiffness, in the extracellular, intracellular, and nuclear compartment contribute and control the resistance of cancer cells to therapy. In this review, we discuss how stiffness of unique tumor components dictates therapy response and what is known about the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

This retrospective study evaluated the expression of β1 integrins and associated proteins as prognostic markers for primary radio(chemo)therapy outcome of patients with locally advanced head and neck squamous cell carcinomas (HNSCC). Tissue microarrays were prepared from 224 HNSCC patients undergoing curative primary radio(chemo)therapy from 1996 to 2005. Staining intensities of β1 integrin and its downstream-proteins FAK, phosphorylated FAK as well as the β1 integrin ECM ligands fibronectin and collagen type-I were determined. Their association to the primary endpoint loco-regional control and the secondary endpoints overall survival and freedom from distant metastasis was analyzed by Cox regression. None of the considered molecular parameters showed a significant association with loco-regional control and freedom from distant metastasis. Patients with p16 positive tumors or tumors with a low intensity of fibronectin showed significantly higher overall survival in univariable regression. In multivariable regression including additional clinical parameters, however, these parameters were not significantly associated with overall survival. Our study in a HNSCC patient cohort treated with primary radio(chemo)therapy does not reveal a prognostic value of β1 integrin expression. [ABSTRACT FROM AUTHOR]

Despite advances in prostate cancer therapy, dissemination and growth of metastases results in shortened survival. Here we examined the potential anti-cancer effect of the NF-κB inhibitor parthenolide (PTL) and its water soluble analogue dimethylaminoparthenolide (DMAPT) on tumour progression and metastasis in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model of prostate cancer. Six-week-old male TRAMP mice received PTL (40 mg/kg in 10% ethanol/saline), DMAPT (100 mg/kg in sterile water), or vehicle controls by oral gavage thrice weekly until palpable tumour formation. DMAPT treatment slowed normal tumour development in TRAMP mice, extending the time-to-palpable prostate tumour by 20%. PTL did not slow overall tumour development, while the ethanol/saline vehicle used to administer PTL unexpectedly induced an aggressive metastatic tumour phenotype. Chronic ethanol/saline vehicle upregulated expression of NF-κB, MMP2, integrin β1, collagen IV, and laminin, and induced vascular basement membrane degradation in primary prostate tumours, as well as increased metastatic spread to the lung and liver. All of these changes were largely prevented by co-administration with PTL. DMAPT (in water) reduced metastasis to below that of water-control. These data suggest that DMAPT has the potential to be used as a cancer preventive and anti-metastatic therapy for prostate cancer. Although low levels of ethanol consumption have not been shown to strongly correlate with prostate cancer epidemiology, these results would support a potential effect of chronic low dose ethanol on metastasis and the TRAMP model provides a useful system in which to further explore the mechanisms involved. [ABSTRACT FROM AUTHOR]

Cell adhesion-mediated resistance limits the success of cancer therapies and is a great obstacle to overcome in the clinic. Since the 1990s, where it became clear that adhesion of tumor cells to the extracellular matrix is an important mediator of therapy resistance, a lot of work has been conducted to understand the fundamental underlying mechanisms and two paradigms were deduced: cell adhesion-mediated radioresistance (CAM-RR) and cell adhesion-mediated drug resistance (CAM-DR). Preclinical work has evidently demonstrated that targeting of integrins, adapter proteins and associated kinases comprising the cell adhesion resistome is a promising strategy to sensitize cancer cells to both radiotherapy and chemotherapy. Moreover, the cell adhesion resistome fundamentally contributes to adaptation mechanisms induced by radiochemotherapy as well as molecular drugs to secure a balanced homeostasis of cancer cells for survival and growth. Intriguingly, this phenomenon provides a basis for synthetic lethal targeted therapies simultaneously administered to standard radiochemotherapy. In this review, we summarize current knowledge about the cell adhesion resistome and highlight targeting strategies to override CAM-RR and CAM-DR. [ABSTRACT FROM AUTHOR]

Each year more than 450,000 Germans are expected to be diagnosed with cancer subsequently receiving standard multimodal therapies including surgery, chemotherapy and radiotherapy. On top, molecular-targeted agents are increasingly administered. Owing to intrinsic and acquired resistance to these therapeutic approaches, both the better molecular understanding of tumor biology and the consideration of alternative and complementary therapeutic support are warranted and open up broader and novel possibilities for therapy personalization. Particularly the latter is underpinned by the increasing utilization of non-invasive complementary and alternative medicine by the population. One investigated approach is the application of low-dose electromagnetic fields (EMF) to modulate cellular processes. A particular system is the BEMER therapy as a Physical Vascular Therapy for which a normalization of the microcirculation has been demonstrated by a low-frequency, pulsed EMF pattern. Open remains whether this EMF pattern impacts on cancer cell survival upon treatment with radiotherapy, chemotherapy and the molecular-targeted agent Cetuximab inhibiting the epidermal growth factor receptor. Using more physiological, three-dimensional, matrix-based cell culture models and cancer cell lines originating from lung, head and neck, colorectal and pancreas, we show significant changes in distinct intermediates of the glycolysis and tricarboxylic acid cycle pathways and enhanced cancer cell radiosensitization associated with increased DNA double strand break numbers and higher levels of reactive oxygen species upon BEMER treatment relative to controls. Intriguingly, exposure of cells to the BEMER EMF pattern failed to result in sensitization to chemotherapy and Cetuximab. Further studies are necessary to better understand the mechanisms underlying the cellular alterations induced by the BEMER EMF pattern and to clarify the application areas for human disease. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate matrix metalloproteinase (MMP) activity and invasion after ionizing radiation (IR) exposure and to determine whether MMP could be epigenetically modulated by histone deacetylase (HDAC) inhibition. Material and methods: Two human breast cancer cell lines (MDA-MB-231 and MCF-7) were cultured in monolayer (2D) and in laminin-rich extracellular matrix (3D). Invasion capability, collagenolytic and gelatinolytic activity, MMP and TIMP protein and mRNA expression and clonogenic survival were analyzed after IR exposure, with and without a HDAC inhibition treatment [1.5 mM valproic acid (VA) or 1 μM trichostatin-A (TSA)]. Results: IR exposure resulted in cell line-dependent stimulation of invasion capacity. In contrast to MCF-7 cells, irradiated MDA-MB-231 showed significantly enhanced mRNA expression ofmmp-1,mmp-3andmmp-13and of their regulatorstimp-1andtimp-2relative to unirradiated controls. This translated into increased collagenolytic and gelatinolytic activity and could be reduced after valproic acid (VA) treatment. Additionally, VA also mitigated IR-enhancedmmpandtimpmRNA expression as well as IR-increased invasion capability. Finally, our data confirm the radiosensitizing effect of VA. Conclusion: These results suggest that IR cell line-dependently induces upregulation of MMP mRNA expression, which appears to be mechanistically linked to a higher invasion capability that is modifiable by HDAC inhibition. [ABSTRACT FROM AUTHOR]

Malignant tumors often show radio- and chemoresistance phenotypes resulting from genetic mutations and epigenetic regulation. As molecular examinations for therapy optimization in patients and animal models are often challenging or infeasible, matrix-based 3-dimensional (3D) cell culture models have been developed as powerful tools in translational research to unravel the mechanisms of cancer cell survival, proliferation and metastasis as well as to identify potential cancer targets. [ABSTRACT FROM AUTHOR]

1. Variation in larval food composition can have far-reaching effects on the adult phenotype of insects. To maximise reproductive output, it is therefore beneficial if insects are able to plastically adapt to nutritional cues in their larval diet. 2. The expression of sexual traits implicated in pre- and postcopulatory sexual selection of the lesser wax moth, Achroia grisella Fabricius, across different rearing environments of varying diet composition was investigated . 3. Moths reared on diet with relatively low amounts of carbohydrate, but more protein and fats, had lower survival rates, decreased body mass, and longer development times. Males reared on this diet produced songs with higher pulse pair rates (which are attractive to females) and transferred more sperm per copulation than males reared on the alternative diets. 4. There was no evidence for a trade-off between pre- and postcopulatory traits. Interestingly, individuals with both higher pulse pair rates and more transferred sperm came from the treatment group with higher mortality rates and generally poorer development. The present results suggest that both of these sexual characteristics are developmentally plastic, but that only moths reared on the protein-rich diet were able to benefit from this plasticity. [ABSTRACT FROM AUTHOR]

In many species, males possess conspicuous characteristics to attract females. These traits often attract predators as well, and males thus may have to balance the conspicuousness of their signals in relation to the prevailing predation risk. Here we develop a theoretical model of optimal signaling and risk-taking behavior for males differing in the attractiveness of their signals. All else being equal, more attractive males should behave more cautiously. Yet this prediction may drastically change if males differ in any additional characteristic, especially if basal mortality rate or signaling costs are higher or if the vulnerability to predators is lower for attractive males. A key insight from our model is that male competition will create a positive feedback so that selection on male risk-taking strategies is acting in opposite directions. If selection acts on one male type to behave more cautiously, this will strengthen selection on males of the other types to take higher risks and vice versa. Our results further demonstrate that the asset-protection principle, which states that individuals with higher future expectations should behave more cautiously, may often be violated. We also offer an alternative to the handicap principle explaining the often found positive association between male ornamentation and viability: attractive males may simply behave more cautiously. [ABSTRACT FROM AUTHOR]

Purpose: Epidermal growth factor receptor (EGFR) is critically involved in progression and therapy resistance of squamous cell carcinoma (SCC). Albeit EGFR targeting could improve the effect of radiotherapy on patients' outcome, the clinical results failed to meet expectations from preclinical studies. In this work, we evaluated the potential of the radionuclide Yttrium-90 (90Y) bound to Cetuximab (90Y-Cetuximab) as novel targeting approach for SCC cells in vitro. Materials and methods: FaDu and A431 cell lines were used. EGFR subcellular localization, clonogenic survival, radiation-induced γH2AX foci and EGFR signaling were examined. Cells were treated with DTPA, DTPA-Cetuximab, 90Y and 90Y-Cetuximab alone or in combination with external X-ray irradiation. Results: Dose- and cell line-dependently, 90Y-Cetuximab mediated a significant reduction in clonogenicity relative to unbound 90Y. Combined 2-Gy external radiation plus 2-Gy equivalent dose of 90Y-Cetuximab was more effective than equivalent doses of 90Y and X-ray radiation. Analogous effects were observed in the number of residual radiation-induced foci. Additionally, EGFR, ERK1/2 and AKT phosphorylation showed alterations upon different treatments. Conclusions: Our findings show that Cetuximab-conjugated 90Y has a significant potential to eradicate human SCC cells. A combination of radioimmunotherapeutic compounds and external radiotherapy might be a promising treatment strategy for clinical application. [ABSTRACT FROM AUTHOR]

In polyandrous species, male reproductive success will at least partly be determined by males' success in sperm competition. To understand the potential for post-mating sexual selection, it is therefore important to assess the extent of female remating. In the lekking moth Achroia grisella, male mating success is strongly determined by female choice based on the attractiveness of male ultrasonic songs. Although observations have indicated that some females will remate, only little is known about the level of sperm competition. In many species, females are more likely to remate if their first mating involved an already mated male than if the first male was virgin. Potentially, this is because mated males are less well able to provide an adequate sperm supply, nutrients, or substances inhibiting female remating. This phenomenon will effectively reduce the strength of pre-copulatory sexual selection because attractive males with high mating success will be more susceptible to sperm competition. We therefore performed an experiment designed both to provide a more precise estimate of female remating probability and simultaneously to test the hypothesis that female remating is influenced by male mating history. Overall, approximately one of five females remated with a second male. Yet, although females mated to non-virgin males were somewhat more prone to remate, the effect of male mating history was not significant. The results revealed, however, that heavier females were more likely to remate. Furthermore, we found that females' second copulations were longer, suggesting that, in accordance with theory, males may invest more sperm in situations with an elevated risk of sperm competition. [ABSTRACT FROM AUTHOR]

Calling a mate can be dangerous for insects, but that does not stop attractive wax moths from singing even when they hear a bat call. Theoretically, unattractive males should take higher risks because they have less to lose, instead they behave more cautiously. A reason for this difference in behavior could be that attractive moths exhaust themselves quickly and try to find a mate while they still can. Unattractive moths can afford to wait.Individuals often have to balance the costs of risky behavior against the potential benefits they may gain from it. This trade-off is especially obvious in the interplay between natural and sexual selection because traits for mate attraction may attract predators as well. In the lesser wax moth Achroia grisella, ultrasonic sexual signaling comes with such a risk because calling for mates also attracts predatory bats. Attractive males should behave more cautiously than unattractive males under such circumstances, as they can expect more future mating opportunities and therefore have more to lose (the so-called asset protection principle). Contrary to these predictions, we found that pulse pair rate and peak amplitude, 2 song components attractive to females, correlated negatively with the duration of a silence response which is displayed when courtship song is experimentally overlayed with the search signal of a predator, the greater horseshoe bat. More attractive males thus recommence singing sooner than less attractive males. Although this is not in line with the asset protection principle, we discuss 3 different ways in which these distinct behavioral differences might be explained: 1) attractive males are in better condition and thus can more easily evade predators, 2) attractive signals are costly in terms of reduced life expectancy, and 3) risk-taking may in itself be a sexually selected trait and as such act as an honest signal of male quality. [ABSTRACT FROM PUBLISHER]

Simple Summary: Pancreatic cancer is the fourth leading cause of cancer-related death in Western countries. Although several therapeutic strategies have been developed for pancreatic cancer, radiation therapy has not yet yielded satisfactory results. Unraveling the mechanism of radioresistance in pancreatic cancer and developing new therapeutic targets has become a major challenge. Therefore, we applied kinome-wide CRISPR-Cas9 loss-of-function screening combined with the 3D cell culture method and identified DYRK1A as a sensitive target for radiotherapy. Additionally, we confirmed that DYRK1A-targeted inhibitors could enhance the efficacy of radiotherapy. Our results further support the use of CRISPR-Cas9 screening to identify novel therapeutic targets and develop new strategies to enhance radiotherapy efficacy in pancreatic cancer. Although radiation therapy has recently made great advances in cancer treatment, the majority of patients diagnosed with pancreatic cancer (PC) cannot achieve satisfactory outcomes due to intrinsic and acquired radioresistance. Identifying the molecular mechanisms that impair the efficacy of radiotherapy and targeting these pathways are essential to improve the radiation response of PC patients. Our goal is to identify sensitive targets for pancreatic cancer radiotherapy (RT) using the kinome-wide CRISPR-Cas9 loss-of-function screen and enhance the therapeutic effect through the development and application of targeted inhibitors combined with radiotherapy. We transduced pancreatic cancer cells with a protein kinase library; 2D and 3D library cells were irradiated daily with a single dose of up to 2 Gy for 4 weeks for a total of 40 Gy using an X-ray generator. Sufficient DNA was collected for next-generation deep sequencing to identify candidate genes. In this study, we identified several cell cycle checkpoint kinases and DNA damage related kinases in 2D- and 3D-cultivated cells, including DYRK1A, whose loss of function sensitizes cells to radiotherapy. Additionally, we demonstrated that the harmine-targeted suppression of DYRK1A used in conjunction with radiotherapy increases DNA double-strand breaks (DSBs) and impairs homologous repair (HR), resulting in more cancer cell death. Our results support the use of CRISPR-Cas9 screening to identify new therapeutic targets, develop radiosensitizers, and provide novel strategies for overcoming the tolerance of pancreatic cancer to radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Cyclin-dependent kinase 2 (CDK2) is critically involved in cell cycling and has been proposed as a potential cancer target. It remains largely elusive whether CDK2 targeting alters the tumor cell radiosensitivity. Materials and methods: CDK2-/- and wild type (WT) mouse embryonic fibroblasts (MEF) as well as six human head and neck squamous cell carcinoma (HNSCC) cell lines (SAS, FaDu, Cal-33, HSC-4, UTSCC-5, UTSCC-8) were used. Upon CDK2 knockdown using small interfering technology, colony formation, DNA double-strand breaks (DSB), cell cycle distribution and expression and phosphorylation of major proteins regulating cell cycle and DNA damage repair were examined. Results: CDK2-/- MEF and CDK2 HNSCC knockdown cell cultures were more radiosensitive than the corresponding controls. Repair of DSB was attenuated under CDK2 knockout or knockdown. In contrast to data in MEF, combined CDK2 knockdown with irradiation showed no cell cycling alterations in SAS and FaDu cultures. Importantly, CDK2 knockdown failed to radiosensitize SAS and FaDu when cultured in a more physiological three-dimensional (3D) extracellular matrix environment. Conclusions: Our findings suggest that targeting of CDK2 radiosensitizes HNSCC cells growing as monolayer. Additional studies performed under more physiological conditions are warranted to clarify the potential of CDK2 as target in radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Radiotherapy of malignant gliomas may be limited by an interference of radiation with the migratory potential of tumor cells. Therefore, the influence of conventional photon and modern carbon ion (12C) irradiation on glioblastoma cell migration and on epidermal growth factor receptor-related (EGFR) signaling was investigated in vitro. Materials and methods: EGFR overexpressing glioblastoma cell lines U87 EGFR++ and LN229 EGFR++ were irradiated with 0, 2 or 6 Gy photons or 12C heavy ions. Migration was analyzed 24 h after treatment in a standardized Boyden Chamber assay. At different time points EGFR, protein kinase B (PKB/AKT) and extracellular signal-related kinases (ERK1/2) were analyzed by Western blotting. Results: 2 Gy photon irradiation increased U87 EGFR++ migration and decreased motility of LN229 EGFR++ cells. Heavy ions decreased migration of both cell lines as a function of dose. There was a time-dependent increase of phosphorylation of EGFR, AKT and ERK1/2 in U87 EGFR++ after 2 Gy photon irradiation. After heavy ion irradiation EGFR, AKT or ERK1/2 remained unchanged. Conclusions: Results suggest that the impact of irradiation on tumor cell migration depends on radiation type and cell line. Photons, but not heavy ions, potentially contribute to treatment failure by increasing EGFR-related tumor cell migration. [ABSTRACT FROM AUTHOR]

Behaviors that appear to be plastic may well be determined by environmental influences during development. Being able to produce a wide range of variants of one kind of behavior, e.g., a very short and a very long response time to a stimulus under different environmental conditions, can be described as behavioral plasticity. How such behavioral reaction norms develop for individuals is poorly understood, but several factors are likely to play a role. We investigated what factors may affect how the risk-taking behavior of the lesser wax moth, Achroia grisella, is shaped during ontogeny. We manipulated larval density to represent the potential intensity of future competition for females in a lek of males, determined adult moths' reaction to predator signals, and tested for plasticity in the silence response, i.e., the acoustic evasion behavior of the moths during the experiments. While we found no effect of larval density on either the probability or the duration of the silence response, 11 % of the variance in duration could be explained by differences between families, and 30 % of the variance was the result of differences between individuals. We found evidence for habituation to the predator signal, clearly indicating that the silence response is a plastic-enough trait to be adjustable to the immediate environment. These results suggest that the degree to which individuals take risks in the context of acoustic signaling depends more on the immediate context and, possibly, genetic differentiation than it is a product of adaptive developmental plasticity. [ABSTRACT FROM AUTHOR]

Cell-cell contact is thought to be critically involved in mechanisms leading to radioresistance. Here, we assessed the influence of confluent compared to subconfluent cell culture conditions and the radiosensitizing ability of E-cadherin inhibition alone or in combination with C225-mediated EGFR inhibition in human squamous cell carcinoma cells. Our results show higher radioresistance under subconfluent growth conditions than under confluency. Delayed plating only resulted in higher radiation survival in confluently growing cells. While E-cadherin depletion significantly reduced basal clonogenic survival, increased the rate of apoptosis, and diminished cell adhesion, the cellular radiosensitivity remained unchanged under both subconfluent and confluent conditions. C225 decreased basal cell survival but failed to modify radiation survival. Additional treatment of E-cadherin knockdown cell cultures with C225 did not further reduce basal cell survival or lead to radiosensitization. Interestingly, E-cadherin silencing in 3D cell cultures did not alter radiosensitivity. Our data indicate that cell-cell contact and E-cadherin are not prominently involved in the regulation of radioresistance of human squamous cell carcinoma cells. In addition, no regulatory interaction between E-cadherin and EGFR in the radiation response was observed. [ABSTRACT FROM AUTHOR]

Altered cell motility is considered to be a key factor in determining tumor invasion and metastasis. Epidermal growth factor (EGF) signaling has been implicated in this process by affecting cytoskeletal organization and dynamics in multiple ways. To sort the temporal and spatial regulation of EGF-dependent cytoskeletal re-organization in relation to a cell's motile behavior time-lapse microscopy was performed on EGF-responsive gastric carcinoma-derived MKN1 cells co-expressing different fluorescently labeled cytoskeletal filaments and focal adhesion components in various combinations. The experiments showed that EGF almost instantaneously induces a considerable increase in membrane ruffling and lamellipodial activity that can be inhibited by Cetuximab EGF receptor antibodies and is not elicited in non-responsive gastric carcinoma Hs746T cells. The transient cell extensions are rich in actin but lack microtubules and keratin intermediate filaments. We show that this EGF-induced increase in membrane motility can be measured by a simple image processing routine. Microtubule plus- ends subsequently invade growing cell extensions, which start to accumulate focal complexes at the lamellipodium- lamellum junction. Such paxillin-positive complexes mature into focal adhesions by tyrosine phosphorylation and recruitment of zyxin. These adhesions then serve as nucleation sites for keratin filaments which are used to enlarge the neighboring peripheral keratin network. Focal adhesions are either disassembled or give rise to stable zyxin-rich fibrillar adhesions which disassemble in the presence of EGF to support formation of new focal adhesion sites in the cell periphery. Taken together the results serve as a basis for modeling the early cytoskeletal EGF response as a tightly coordinated and step-wise process which is relevant for the prediction of the effectiveness of anti-EGF receptor-based tumor therapy. [ABSTRACT FROM AUTHOR]

Cell morphology determines cell behavior, signal transduction, protein-protein interaction, and responsiveness to external stimuli. In cancer, these functions profoundly contribute to resistance mechanisms to radio- and chemotherapy. With regard to this aspect, this study compared the genome wide gene expression in exponentially growing cell lines from different tumor entities, lung carcinoma and squamous cell carcinoma, under more physiological three-dimensional (3D) versus monolayer cell culture conditions. Whole genome cDNA microarray analysis was accomplished using the Affymetrix HG U133 Plus 2.0 gene chip. Significance analysis of microarray (SAM) and t-test analysis revealed significant changes in gene expression profiles of 3D relative to 2D cell culture conditions. These changes affected the extracellular matrix and were mainly associated with biological processes like tissue development, cell adhesion, immune system and defense response in contrast to terms related to DNA repair, which lacked significant alterations. Selected genes were verified by semiquantitative RT-PCR and Western blotting. Additionally, we show that 3D growth mediates a significant increase in tumor cell radio- and chemoresistance relative to 2D. Our findings show significant gene expression differences between 3D and 2D cell culture systems and indicate that cellular responsiveness to external stress such as ionizing radiation and chemotherapeutics is essentially influenced by differential expression of genes involved in the regulation of integrin signaling, cell shape and cell-cell contact. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Propolis, a product of honeybees, has anti-tumoural, cytotoxic, anti-metastatic and anti-inflammatory properties. The aim of this study was the evaluation of the radiosensitising capacity of Propolis in human head and neck squamous cell carcinoma (HNSCC) cells. Materials and methods: HNSCC cell lines (FaDu, UT-SCC15, UT-SCC45), fibroblasts (HSF2) and keratinocytes (HaCaT) were treated with Propolis (0--250 μμg/ml; 1, 4, 24 h) without and in combination with X-rays (0--6 Gy, single dose). Clonogenic survival, proliferation, apoptosis, expression and phosphorylation of different signalling proteins were determined. Liquid chromatography-mass spectrometry (LC-MS) was performed on Propolis. Results: Propolis significantly ( P < 0.01) reduced cell growth and clonogenic survival in a time- and concentration-dependent manner. Propolis-induced apoptosis and Caspase 3 cleavage, increased phosphorylation of Extracellular signal Regulated Kinase 1/2 (ERK1/2), protein kinase B/Akt1 (Akt1) and Focal adhesion kinase (FAK). While a 1-h Propolis pretreatment was ineffective, a 3-h pretreatment significantly ( P < 0.05) radiosensitised FaDu cells. LC-MS analysis identified 14 compounds of Propolis. Conclusions: Our data show that Propolis exerts cytotoxicity in a concentration- and time-dependent manner. In one out of three HNSCC cell lines, Propolis also caused an enhancement of radiosensitivity. Future studies on Propolis will shed further light on its potential as an adjuvant to radiotherapy. [ABSTRACT FROM AUTHOR]

Bumble bees (Bombus) are vitally important pollinators of wild plants and agricultural crops worldwide. Fragmentary observations. however, have suggested population declines in several North American species. Despite rising concern over these observations in the United States, highlighted in a recent National Academy of Sciences report, a national assessment of the geographic scope and possible causal factors of bumble bee decline is lacking. Here, we report results of a 3-y interdisciplinary study of changing distributions, population genetic structure, and levels of pathogen infection in bumble bee populations across the United States. We compare current and historical distributions of eight species, compiling a database of >73,000 museum records for comparison with data from intensive nationwide surveys of >16,000 specimens. We show that the relative abundances of four species have declined by up to 96% and that their surveyed geographic ranges have contracted by 23- 87%, some within the last 20 y. We also show that declining populations have significantly higher infection levels of the microsporidian pathogen Nosema bombi and lower genetic diversity compared with co-occurring populations of the stable (nondeclining) species. Higher pathogen prevalence and reduced genetic diversity are, thus, realistic predictors of these alarming patterns of decline in North America, although cause and effect remain uncertain. [ABSTRACT FROM AUTHOR]

Focal adhesion (FA) signaling mediated by adhesion to extracellular matrix and growth factor receptors contributes to the regulation of the cellular stress response to external stimuli. Critical to focal adhesion assembly and signaling is the adapter protein PINCH1. To evaluate whether the prosurvival function of PINCH1 in radiation cell survival depends on cell adhesion, we examined PINCH1fl/fl and PINCH1-/- mouse embryonic fibroblasts and human cancer cell lines. Here, we found that the enhanced cellular radiosensitivity mediated by PINCH1 depletion observed under adhesion conditions is conserved when cells are irradiated under suspension conditions. This unsuspected finding could not be explained by the observed modification of adhesion and growth factor associated signaling involving FAK, Paxillin, p130CAS, Src, AKT, GSK3β and ERK1/ 2 under suspension and serum withdrawal relative to adhesion conditions with serum. Our data suggest that the adapter protein PINCH1 critically participates in the regulation of the cellular radiosensitivity of normal and malignant cells similarly under adhesion and suspension conditions. [ABSTRACT FROM AUTHOR]

Purpose: Integrin-Linked Kinase (ILK) is associated with integrin and growth factor receptor signalling. As both signalling pathways contribute to cancer cell resistance, ILK seems well suited as a promising tumour target. Material and methods: Data were obtained by performing a PubMed database search and summarised with a focus on the function of ILK in cancer biology. Results: The findings on the catalytic function of ILK, on the putative substrates of ILK and on the expression of ILK in tumour and normal tissues are heterogeneous. In the context of cancer, two of these issues might be of importance. First, a variety of reports indicate a lack of ILK overexpression in tumours. Second, wild-type or overexpression of ILK has been found to considerably sensitise tumour cells to ionising irradiation as compared to ILK knockout or ILK knockdown conditions. In contrast, wild-type or overexpression of ILK has been shown to protect tumour cells from chemotherapy-induced cell death. Conclusions: Due to these conflicting data, it is difficult to evaluate if therapeutic targeting of ILK is a reasonable strategy in cancer therapy. A more comprehensive understanding of the molecular mechanisms controlled by ILK may help to answer this question. [ABSTRACT FROM AUTHOR]

Background: The constant increase of cancer cell resistance to radio- and chemotherapy hampers improvement of patient survival and requires novel targeting approaches. Integrin-Linked Kinase (ILK) has been postulated as potent druggable cancer target. On the basis of our previous findings clearly showing that ILK transduces antisurvival signals in cells exposed to ionizing radiation, this study evaluated the impact of the small molecule inhibitor QLT0267, reported as putative ILK inhibitor, on the cellular radiation survival response of human head and neck squamous cell carcinoma cells (hHNSCC). Methodology/Principal Findings: Parental FaDu cells and FaDu cells stably transfected with a constitutively active ILK mutant (FaDu-IH) or empty vectors, UTSCC45 cells, ILKfloxed/floxed(fl/fl) and ILK-/- mouse fibroblasts were used. Cells grew either two-dimensionally (2D) on or three-dimensionally (3D) in laminin-rich extracellular matrix. Cells were treated with QLT0267 alone or in combination with irradiation (X-rays, 0-6 Gy single dose). ILK knockdown was achieved by small interfering RNA transfection. ILK kinase activity, clonogenic survival, number of residual DNA double strand breaks (rDSB; γH2AX/53BP1 foci assay), cell cycle distribution, protein expression and phosphorylation (e.g. Akt, p44/42 mitogen-activated protein kinase (MAPK)) were measured. Data on ILK kinase activity and phosphorylation of Akt and p44/42 MAPK revealed a broad inhibitory spectrum of QLT0267 without specificity for ILK. QLT0267 significantly reduced basal cell survival and enhanced the radiosensitivity of FaDu and UTSCC45 cells in a time- and concentration-dependent manner. QLT0267 exerted differential, cell culture model-dependent effects with regard to radiogenic rDSB and accumulation of cells in the G2 cell cycle phase. Relative to corresponding controls, FaDu-IH and ILKfl/fl fibroblasts showed enhanced radiosensitivity, which failed to be antagonized by QLT0267. A knockdown of ILK revealed no change in clonogenic survival of the tested cell lines as compared to controls. Conclusions/Significance: Our data clearly show that the small molecule inhibitor QLT0267 has potent cytotoxic and radiosensitizing capability in hHNSCC cells. However, QLT0267 is not specific for ILK. Further in vitro and in vivo studies are necessary to clarify the potential of QLT0267 as a targeted therapeutic in the clinic. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma patients suffer from a poor prognosis with a limited survival of just a few months. Incurability of this tumor mainly results from glioblastoma cell invasiveness as well as therapy resistance. A better understanding of the molecular processes driving aggressive infiltration and resistance to therapeutic intervention would enable the development of new therapeutic approaches. In this study, we identify a so-far-undescribed role of the cytoskeleton protein Lamellipodin in glioblastoma cells. We determined that Lamellipodin essentially mediates glioblastoma invasion, proliferation and radiosensitivity. Our results further identify a new Lamellipodin-RICTOR-EGFR signaling axis enabling glioblastoma radiation survival. Glioblastoma is a tumor type of unmet need despite the development of multimodal treatment strategies. The main factors contributing to the poor prognosis of glioblastoma patients are diverse genetic and epigenetic changes driving glioblastoma persistence and recurrence. Complemented are these factors by extracellular cues mediated through cell surface receptors, which further aid in fostering pro-invasion and pro-survival signaling contributing to glioblastoma therapy resistance. The underlying mechanisms conferring this therapy resistance are poorly understood. Here, we show that the cytoskeleton regulator Lamellipodin (Lpd) mediates invasiveness, proliferation and radiosensitivity of glioblastoma cells. Phosphoproteome analysis identified the epidermal growth factor receptor (EGFR) signaling axis commonly hyperactive in glioblastoma to depend on Lpd. Mechanistically, EGFR signaling together with an interaction between Lpd and the Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) jointly regulate glioblastoma radiosensitivity. Collectively, our findings demonstrate an essential function of Lpd in the radiation response and invasiveness of glioblastoma cells. Thus, we uncover a novel Lpd-driven resistance mechanism, which adds an additional critical facet to the complex glioblastoma resistance network. [ABSTRACT FROM AUTHOR]

Purpose: Integrin-linked kinase (ILK) mediates signals from β integrins and links integrins to epidermal growth factor receptor (EGFR). Previous studies have identified an antisurvival effect of ILK in irradiated cells. The aim of this study was to evaluate the role of EGFR tyrosine kinase (tk) activity for ILK-mediated radiosensitization. Materials and methods: Human FaDu squamous cell carcinoma (SCC) cells stably transfected with hyperactive ILK (ILK-hk) and ILKfl/fl and ILK-/- mouse fibroblasts were treated with the pharmacological EGFR-tk inhibitor BIBX1382BS without or in combination with single doses of X-rays. Clonogenic radiation survival, protein expression and phosphorylation (EGFR, v-akt murine thymoma viral oncogene homolog 1 (Akt), p42/44 mitogen-activated protein kinase), DNA-double strand break (DSB) repair measured by γH2AX foci, cell morphology and cell cycle distribution were examined. Results: Expression of ILK-hk or ILKfl/fl status resulted in significant radiosensitization relative to vector controls or ILK-/-. Following BIBX1382BS, clonogenic survival of normal fibroblasts and vector controls remained unaffected while ILK-hk-related radiosensitization was significantly diminished. In contrast to BIBX1382BS, which did not affect DNA-DSB repair, ILK-hk-mediated radiosensitization was associated with reduced DNA-DSB repair. At 10 days after BIBX1382BS treatment, FaDu transfectants, in contrast to fibroblasts, showed reduced cell size, accumulation of G1 phase cells and reduced Akt-serine(S)473 phosphorylation. Conclusions: Our findings confirm ILK as a cell type-independent antisurvival factor in irradiated cells, which actions in terms of radiosensitization critically depend on proper EGFR-tk activity. [ABSTRACT FROM AUTHOR]

Purpose: In addition to focal adhesion kinase (FAK), Paxillin and p130 Crk-associated substrate (p130Cas), integrin-linked kinase (ILK) mediates signals from β integrins for controlling, e.g., survival, adhesion and spreading. To evaluate the role of ILK in the cellular radiosensitivity at different stages of cell adhesion and spreading, ILKfloxed/floxed (fl/fl) and ILK-/- mouse fibroblasts were examined. Materials and methods: Cells were irradiated (0 - 4 Gy, X-rays) in suspension, after varying time periods on fibronectin (FN) or after 24 h on different matrix proteins. Irradiation was combined with phosphatidylinositol-3 kinase (PI3K) inhibition using Ly294002. Clonogenic radiation survival, cell adhesion, and kinetics of protein expression and phosphorylation during FN adhesion (ILK, v-akt murine thymoma viral oncogene homolog 1 (AKT), FAK, Paxillin, p130Cas) were examined. Results: In suspension and during the first hour on FN, irradiated ILKfl/fl cells survived significantly better than ILK-/- cells in a PI3K- and serum-dependent manner. 24-h cell cultures on different matrix proteins showed no difference in radiosensitivity. During FN adhesion, which was slightly impaired in ILK-/- cells, protein kinetics uncovered differences in AKT, FAK, Paxillin and p130Cas phosphorylation in the two cell lines. Phosphorylation of FAK, Paxillin and p130Cas was downregulated upon exposure to ionizing radiation in an ILK-independent manner. Conclusions: These findings indicate a critical function of ILK in the cellular radiosensitivity during the early stages of adhesion to and spreading on FN. On the basis of the presented data, a precise correlation of adhesion-, serum- and PI3K-mediated changes in PI3K/AKT and FAK/Paxillin/p130Cas signaling cascades was not found. However, identifying the underlying mechanisms of adhesion- and spreading-related changes in the cellular radiosensitivity might be relevant for an optimization of radiotherapeutic strategies specifically targeting cells located at the invasive edge of a malignant tumor. [ABSTRACT FROM AUTHOR]

Purpose: Radiation therapy (RT) is a commonly used modality to treat human cancer. However, dose-limiting toxicity and resistance are major problems to improving treatment efficacy. Increasing evidence has pointed to the critical role of the tumor microenvironment and cell-extracellular matrix (ECM), specifically via β1 integrins, in modifying response to therapy, including radiation. β1 integrins have been implicated in several key processes in malignant progression and metastasis, and more recently in mediating resistance to cytotoxic chemotherapy and radiation. Evidence is mounting that β1 integrins mediate essential survival signals post-IR, through both canonical and non-canonical integrin signaling pathways that make it a highly promising therapeutic target for several solid malignancies. Conclusions: In this mini-review article, we briefly summarize the most recent emerging findings concerning β1 integrin and radiation survival that indicate the promise of β1 integrin inhibitory agents as radiosensitizers. [ABSTRACT FROM AUTHOR]

Background: The anticancer drug Ukrain (NSC-631570) which has been specified by the manufacturer as semisynthetic derivative of the Chelidonium majus L. alkaloid chelidonine and the alkylans thiotepa was reported to exert selective cytotoxic effects on human tumour cell lines in vitro. Few clinical trials suggest beneficial effects in the treatment of human cancer. Aim of the present study was to elucidate the importance of apoptosis induction for the antineoplastic activity of Ukrain, to define the molecular mechanism of its cytotoxic effects and to identify its active constituents by mass spectrometry. Methods: Apoptosis induction was analysed in a Jurkat T-lymphoma cell model by fluorescence microscopy (chromatin condensation and nuclear fragmentation), flow cytometry (cellular shrinkage, depolarisation of the mitochondrial membrane potential, caspase-activation) and Western blot analysis (caspase-activation). Composition of Ukrain was analysed by mass spectrometry and LC-MS coupling. Results: Ukrain turned out to be a potent inducer of apoptosis. Mechanistic analyses revealed that Ukrain induced depolarisation of the mitochondrial membrane potential and activation of caspases. Lack of caspase-8, expression of cFLIP-L and resistance to death receptor ligand-induced apoptosis failed to inhibit Ukrain-induced apoptosis while lack of FADD caused a delay but not abrogation of Ukrain-induced apoptosis pointing to a death receptor independent signalling pathway. In contrast, the broad spectrum caspase-inhibitor zVAD-fmk blocked Ukrain-induced cell death. Moreover, over-expression of Bcl-2 or Bcl-xL and expression of dominant negative caspase-9 partially reduced Ukrain-induced apoptosis pointing to Bcl-2 controlled mitochondrial signalling events. However, mass spectrometric analysis of Ukrain failed to detect the suggested trimeric chelidonine thiophosphortriamide or putative dimeric or monomeric chelidonine thiophosphortriamide intermediates from chemical synthesis. Instead, the Chelidonium majus L. alkaloids chelidonine, sanguinarine, chelerythrine, protopine and allocryptopine were identified as major components of Ukrain. Apart from sanguinarine and chelerythrine, chelidonine turned out to be a potent inducer of apoptosis triggering cell death at concentrations of 0.001 mM, while protopine and allocryptopine were less effective. Similar to Ukrain, apoptosis signalling of chelidonine involved Bcl-2 controlled mitochondrial alterations and caspase-activation. Conclusion: The potent proapoptotic effects of Ukrain are not due to the suggested "Ukrainmolecule" but to the cytotoxic efficacy of Chelidonium majus L. alkaloids including chelidonine. [ABSTRACT FROM AUTHOR]

Cell survival and cycling in mammalian cells are both greatly affected by ionizing radiation and are both strictly controlled by integrated integrin-mediated adhesion to extracellular matrix (ECM) proteins and by binding of growth factors to their cognate receptors. Recent emerging findings show a diverse panel of integrin-dependent signals that are channelled into the regulation and modification of the cellular response to ionizing radiation. Cell adhesion-mediated radioresistance and alteration of DNA damage-induced cell cycle arrest in cells attached to the ECM can be linked to focal adhesion protein signalling. This review summarizes the latest radiobiological and radiooncological findings about integrins and their signal transduction pathways. [ABSTRACT FROM AUTHOR]

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