Integrins are heterodimeric transmembrane proteins able to connect cells with the micro‐environment. They represent a family of receptors involved in almost all the hallmarks of cancer. Integrins recognizing the Arg‐Gly‐Asp (RGD) peptide in their natural extracellular matrix ligands have been particularly investigated as tumoral therapeutic targets. In the last 30 years, intense research has been dedicated to designing specific RGD‐like ligands able to discriminate selectively the different RGD‐recognizing integrins. Chemists′ efforts have led to the proposition of modified peptide or peptidomimetic libraries to be used for tumor targeting and/or tumor imaging. Here we review, from the biological point of view, the rationale underlying the need to clearly delineate each RGD‐integrin subtype by selective tools. We describe the complex roles of RGD‐integrins (mainly the most studied αvβ3 and α5β1 integrins) in tumors, the steps towards selective ligands and the current usefulness of such ligands. Although the impact of integrins in cancer is well acknowledged, the biological characteristics of each integrin subtype in a specific tumor are far from being completely resolved. Selective ligands might help us to reconsider integrins as therapeutic targets in specific clinical settings.

The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood-brain barrier and all normal brain cells. It is the result of a dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow. However, cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes' expression involved in cell proliferation, metabolism and angiogenesis and thus, promote tumor expansion, therapeutic resistance and metabolic adaptation. This cellular adaptation implies Hypoxia-Inducible Factors (HIF), namely HIF-1α and HIF-2α. In pediatric high-grade gliomas (pHGGs), several questions remained open on hypoxia-specific role in normal brain during gliomagenesis and pHGG progression, as well how to model it in preclinical studies and how it might be counteracted with targeted therapies. Therefore, this review aims to gather various data about this key extrinsic tumor factor in pHGGs.

Osteosarcoma is the most frequent primary bone tumor diagnosed during adolescence and young adulthood. It is associated with the worst outcomes in the case of poor response to chemotherapy and in metastatic disease. While no molecular biomarkers are clearly and currently associated with those worse situations, the study of pathways involved in the high level of tumor necrosis and in the immune/metabolic intra-tumor environment seems to be a way to understand these resistant and progressive osteosarcomas. In this review, we provide an updated overview of the role of hypoxia in osteosarcoma oncogenesis, progression and during treatment. We describe the role of normoxic/hypoxic environment in normal tissues, bones and osteosarcomas to understand their role and to estimate their druggability. We focus particularly on the role of intra-tumor hypoxia in osteosarcoma cell resistance to treatments and its impact in its endogenous immune component. Together, these previously published observations conduct us to present potential perspectives on the use of therapies targeting hypoxia pathways. These therapies could afford new treatment approaches in this bone cancer. Nevertheless, to study the osteosarcoma cell druggability, we now need specific in vitro models closely mimicking the tumor, its intra-tumor hypoxia and the immune microenvironment to more accurately predict treatment efficacy and be complementary to mouse models.

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Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the subjects of several studies. This work aimed to evaluate molecular and phenotypic changes occurring during and after TMZ treatment in a glioblastoma cell model, the U87MG. These initially TMZ-sensitive cells acquire long-lasting resistance even after removal of the drug. Transcriptomic analysis revealed that profound changes occurred between parental and resistant cells, particularly at the level of the integrin repertoire. Focusing on α5β1 integrin, which we proposed earlier as a glioblastoma therapeutic target, we demonstrated that its expression was decreased in the presence of TMZ but restored after removal of the drug. In this glioblastoma model of recurrence, α5β1 integrin plays an important role in the proliferation and migration of tumoral cells. We also demonstrated that reactivating p53 by MDM2 inhibitors concomitantly with the inhibition of this integrin in recurrent cells may overcome the TMZ resistance. Our results may explain some integrin-based targeted therapy failure as integrin expressions are highly switchable during the time of treatment. We also propose an alternative way to alter the viability of recurrent glioblastoma cells expressing a high level of α5β1 integrin.

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BACKGROUND Glioblastoma (GBM) is the most frequent and deadliest type of central nervous system tumors. Despite the treatment by the Stupp protocol, almost all patients relapse and new therapeutic protocols have been unsuccessful for ameliorating patient survival. Molecular heterogeneity of GBM and existence of glioma stem cells (GSC) may be linked to therapy resistance and recurrence. We demonstrated earlier that α5β1 integrin is a GBM therapeutic target which participate to therapy resistance; a high expression in patient tumors is linked to a worse prognosis. Expression of α5β1 integrin is heterogeneous inter- and intra-tumorally. We particularly addressed the role of glioma stem cell plasticity in the modulation of the integrin expression. Stem cells reside in specific niches (perivascular or hypoxic niches) in the tumor and are at the origin of the more differentiated tumor cell bulk. Metabolism is known to change between the different GSC states and may be affected by or may affect the integrin expression. The aim of our work is therefore to consider the expression of the integrin α5β1 in relationship with GSC differentiation or in hypoxic environment and with cell metabolism. MATERIAL AND METHODS Ten different patient-derived glioma stem cell lines were investigated. Cell culture in stem cell medium (neurospheres) or differentiation medium (adherent cell monolayer) was made in normoxia (21% O2) or hypoxia (1%O2). Alternatively, chemically-induced hypoxia (cobalt chloride/desferoxiamine) was used. Integrin expression was kinetically checked at the mRNA (RT-qPCR) or protein (Western blot) levels. Cell metabolism was investigated with the Seahorse Xfp technology and by HRMAS-NMR. RESULTS No GSC lines (neurospheres) expressed the α5β1 integrin. Interestingly, only half of them did after differentiation suggesting a first level of heterogeneity. A second level of heterogeneity was observed in hypoxic conditions provoking induction of integrin α5β1 expression in only some non-differentiated GSC. Three categories of GSC were thus characterized: one able to express the integrin in hypoxia and after differentiation, one never expressing it and the third one only after differentiation. Cell metabolism differed between GSC before and after differentiation and in presence of integrin α5β1 antagonists. Specific glioma regulator network analysis revealed new targets to be inhibited concomitantly with the integrin. CONCLUSION Data suggest that α5β1 integrin expression may be induced by different signaling pathways. Molecular switches may occur either when stem cells differentiate to tumor cells but also directly in stem cells in hypoxic niches. Characterization of α5β1 integrin expression drivers may help to find new therapeutic targets but also to delineate subpopulation of patients who would benefit from an anti-integrin strategy.