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Solid tumors often grow in a micro-environment characterized by < 2% O 2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild. Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy. We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.

The extracellular signal-related kinases (ERKs) act as pleiotropic molecules in tumors, where they activate pro-survival pathways leading to cell proliferation and migration, as well as modulate apoptosis, differentiation, and senescence. Given its central role as sensor of extracellular signals, ERK transduction system is widely exploited by cancer cells subjected to environmental stresses, such as chemotherapy and anti-tumor activity of the host immune system. Aggressive tumors have a tremendous ability to adapt and survive in stressing and unfavorable conditions. The simultaneous resistance to chemotherapy and immune system responses is common, and ERK signaling plays a key role in both types of resistance. In this review, we dissect the main ERK-dependent mechanisms and feedback circuitries that simultaneously determine chemoresistance and immune-resistance/immune-escape in cancer cells. We discuss the pros and cons of targeting ERK signaling to induce chemo-immune-sensitization in refractory tumors.

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.

Background Nutrient deprivation, hypoxia, radiotherapy and chemotherapy induce endoplasmic reticulum (ER) stress, which activates the so-called unfolded protein response (UPR). Extensive and acute ER stress directs the UPR towards activation of death-triggering pathways. Cancer cells are selected to resist mild and prolonged ER stress by activating pro-survival UPR. We recently found that drug-resistant tumor cells are simultaneously resistant to ER stress-triggered cell death. It is not known if cancer cells adapted to ER stressing conditions acquire a chemoresistant phenotype. Methods To investigate this issue, we generated human cancer cells clones with acquired resistance to ER stress from ER stress-sensitive and chemosensitive cells. Results ER stress-resistant cells were cross-resistant to multiple chemotherapeutic drugs: such multidrug resistance (MDR) was due to the overexpression of the plasma-membrane transporter MDR related protein 1 (MRP1). Gene profiling analysis unveiled that cells with acquired resistance to ER stress and chemotherapy share higher expression of the UPR sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK), which mediated the erythroid-derived 2-like 2 (Nrf2)-driven transcription of MRP1. Disrupting PERK/Nrf2 axis reversed at the same time resistance to ER stress and chemotherapy. The inducible silencing of PERK reduced tumor growth and restored chemosensitivity in resistant tumor xenografts. Conclusions Our work demonstrates for the first time that the adaptation to ER stress in cancer cells produces a MDR phenotype. The PERK/Nrf2/MRP1 axis is responsible for the resistance to ER stress and chemotherapy, and may represent a good therapeutic target in aggressive and resistant tumors.

The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.

Angiogenesis requires the temporal coordination of the proliferation and the migration of endothelial cells. Here, we investigated the regulatory role of microRNAs (miRNAs) in harmonizing angiogenesis processes in a three-dimensional in vitro model. We described a microRNA network which contributes to the observed down- and upregulation of proliferative and migratory genes, respectively. Global analysis of miRNA–target gene interactions identified two sub-network modules, the first organized in upregulated miRNAs connected with downregulated target genes and the second with opposite features. miR-424–5p and miR-29a-3p were selected for the network validation. Gain- and loss-of-function approaches targeting these microRNAs impaired angiogenesis, suggesting that these modules are instrumental to the temporal coordination of endothelial migration and proliferation. Interestingly, miR-29a-3p and its targets belong to a selective biomarker that is able to identify colorectal cancer patients who are responding to anti-angiogenic treatments. Our results provide a view of higher-order interactions in angiogenesis that has potential to provide diagnostic and therapeutic insights.

Background Invasive micropapillary carcinoma (IMPC) of the breast is a distinct and aggressive variant of luminal type B breast cancer that does not respond to neoadjuvant chemotherapy. It is characterized by small pseudopapillary clusters of cancer cells with inverted cell polarity. To investigate whether hypoxia-inducible factor-1 (HIF-1) activation may be related to the drug resistance described in this tumor, we used MCF7 cancer cells cultured as 3-D spheroids, which morphologically simulate IMPC cell clusters. Methods HIF-1 activation was measured by EMSA and ELISA in MCF7 3-D spheroids and MCF7 monolayers. Binding of HIF-1α to MDR-1 gene promoter and modulation of P-glycoprotein (Pgp) expression was evaluated by ChIP assay and FACS analysis, respectively. Intracellular doxorubicin retention was measured by spectrofluorimetric assay and drug cytotoxicity by annexin V-FITC measurement and caspase activity assay. Results In MCF7 3-D spheroids HIF-1 was activated and recruited to participate to the transcriptional activity of MDR-1 gene, coding for Pgp. In addition, Pgp expression on the surface of cells obtained from 3-D spheroids was increased. MCF7 3-D spheroids accumulate less doxorubicin and are less sensitive to its cytotoxic effects than MCF7 cells cultured as monolayer. Finally, HIF-1α inhibition either by incubating cells with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (a widely used HIF-1α inhibitor) or by transfecting cells with specific siRNA for HIF-1α significantly decreased the expression of Pgp on the surface of cells and increased the intracellular doxorubicin accumulation in MCF7 3-D spheroids. Conclusions MCF7 breast cancer cells cultured as 3-D spheroids are resistant to doxorubicin and this resistance is associated with an increased Pgp expression in the plasma membrane via activation of HIF-1. The same mechanism may be suggested for IMPC drug resistance.

Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation. γδT cells are activated by phosphoantigens, and ABCA1 is involved in cholesterol transport. Here the authors link these ideas to show that ABCA1, apoA-I and BTN3A1 regulate extracellular phosphoantigen release by dendritic cells, and implicate ABCA1 in mevalonate-mediated activation of Vγ9Vδ2 T cells.

Vγ9Vδ2 T cells are non-conventional T cells with a natural inclination to recognize and kill cancer cells. Malignant B cells, including myeloma cells, are privileged targets of Vγ9Vδ2 T cells . However, this inclination is often lost due to multiple mechanisms mediated by tumor cells and local microenvironment. Multiple myeloma (MM) is a paradigm disease in which antitumor immunity is selectively impaired at the tumor site. By interrogating the immune reactivity of bone marrow (BM) Vγ9Vδ2 T cells to phosphoantigens, we have revealed a very early and long-lasting impairment of Vγ9Vδ2 T-cell immune functions which is already detectable in monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even in clinical remission after autologous stem cell transplantation. Multiple cell subsets [MM cells, myeloid-derived suppressor cells, regulatory T cells, and BM-derived stromal cells (BMSC)] are involved in Vγ9Vδ2 T-cell inhibition several immune suppressive mechanisms including the redundant expression of multiple immune checkpoints (ICPs). This review will address some aspects related to the dynamics of ICP expression in the BM of MM patients in relationship to the disease status (MGUS, diagnosis, remission, and relapse) and how this multifaceted ICP expression impairs Vγ9Vδ2 T-cell function. We will also provide some suggestions how to rescue Vγ9Vδ2 T cells from the immune suppression operated by ICP and to recover their antimyeloma immune effector functions at the tumor site.