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Cycling hypoxia (cyH), neo-angiogenesis, and tumor-associated macrophages are key features of the tumor microenvironment. In this study, we demonstrate that cyH potentiates the induction by unpolarized and M1-like macrophages of endothelial inflammatory phenotype and adhesiveness for monocytes and cancer cells. This process triggers a positive feedback loop sustaining tumor inflammation. This work opens the door for innovative therapeutic strategies to treat tumor inflammation and metastasis.In cancers, the interaction between macrophages and endothelial cells (ECs) regulates tumor inflammation and metastasis. These cells are both affected by cycling hypoxia (cyH), also called intermittent hypoxia, a feature of the tumor microenvironment. cyH is also known to favor tumor inflammation and metastasis. Nonetheless, the potential impact of cyH on the dialog between macrophages and ECs is still unknown. In this work, the effects of unpolarized, M1-like, and M2-like macrophages exposed to normoxia, chronic hypoxia (chH), and cyH on endothelial adhesion molecule expression, pro-inflammatory gene expression, and EC adhesiveness for monocytes and cancer cells were investigated. cyH increased the ability of unpolarized and M1-like macrophages to induce EC inflammation and to increase the expression of the EC endothelial adhesion molecule ICAM1, respectively. Unpolarized, M1-like, and M2-like macrophages were all able to promote EC adhesive properties toward cancer cells. Furthermore, the ability of macrophages (mostly M1-like) to shift EC phenotype toward one allowing cancer cell and monocyte adhesion onto ECs was potentiated by cyH. These effects were specific to cyH because they were not observed with chH. Together, these results show that cyH amplifies the effects of macrophages on ECs, which may promote tumor inflammation and metastasis.

Background and Purpose: The anti-diabetic biguanide drugs metformin and phenformin exhibit antitumor activity in various models. However, their radiomodulatory effect under hypoxic conditions, particularly for phenformin, is largely unknown. This study therefore examines whether metformin and phenformin as mitochondrial complex I blockades could overcome hypoxic radioresistance through inhibition of oxygen consumption. Materials and Methods: A panel of colorectal cancer cells (HCT116, DLD-1, HT29, SW480, and CT26) was exposed to metformin or phenformin for 16 h at indicated concentrations. Afterward, cell viability was measured by MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) were detected by flow cytometry. Phosphorylation of AMP-activated protein kinase (AMPK) was examined by western blot. Mitochondria complexes activity and oxygen consumption rate (OCR) were measured by seahorse analyzer. The radiosensitivity of tumor cells was assessed by colony formation assay under aerobic and hypoxic conditions. The in vitro findings were further validated in colorectal CT26 tumor model. Results: Metformin and phenformin inhibited mitochondrial complex I activity and subsequently reduced OCR in a dose-dependent manner starting at 3 mM and 30 μM, respectively. As a result, the hypoxic radioresistance of tumor cells was counteracted by metformin and phenformin with an enhancement ratio about 2 at 9 mM and 100 μM, respectively. Regarding intrinsic radioresistance, both of them did not exhibit any effect although there was an increase of phosphorylation of AMPK and ROS production. In tumor-bearing mice, metformin or phenformin alone did not show any anti-tumor effect. While in combination with radiation, both of them substantially delayed tumor growth and enhanced radioresponse, respectively, by 1.3 and 1.5-fold. Conclusion: Our results demonstrate that metformin and phenformin overcome hypoxic radioresistance through inhibition of mitochondrial respiration, and provide a rationale to explore metformin and phenformin as hypoxic radiosensitizers.

Photodynamic therapy (PDT) is used to treat malignancies and precancerous lesions. Near-infrared light delivered by lasers was thought for a while to be the most appropriate option to activate photosensitizers, mostly porphyrins, in the depth of the diseased tissues. More recently, however, several advantages including low cost and reduced adverse effects led to consider light emitting diodes (LED) and even daylight as an alternative to use PDT to treat accessible lesions. In this study we examined the capacity of OR141, a recently identified non-porphyrin photosensitizer (PS), to exert significant cytotoxic effects in various models of skin lesions and tumors upon white light activation. Using different cancer cell lines, we first identified LED lamp as a particularly suited source of light to maximize anti-proliferative effects of OR141. We then documented that OR141 diffusion and light penetration into tumor spheroids both reached thresholds compatible with the induction of cell death deep inside these 3D culture models. We further identified Arlasove as a clinically suitable solvent for OR141 that we documented by using Franz cells to support significant absorption of the PS through human skin. Finally, using topical but also systemic administration, we validated growth inhibitory effects of LED-activated OR141 in mouse skin tumor xenograft and precancerous lesions models. Altogether these results open clinical perspectives for the use of OR141 as an attractive PS to treat superficial skin malignant and non-malignant lesions using affordable LED lamp for photoactivation.

In recent clinical studies, vascular disrupting agents (VDAs) are mainly used in combination with chemotherapy. However, an often overlooked concern in treatment combination is the VDA-induced impairment of chemotherapy distribution in the tumor. The work presented here investigated the impact of blood flow shutdown induced by Combretastatin A4 (CA4) on gemcitabine uptake into mouse hepatocarcinoma. At 2 hours after CA4 treatment, using DCE-MRI, a significant decrease in the perfusion-relevant parameters Ktrans and Vp were observed in treated group compared with the control group. The blood flow shutdown was indeed confirmed by a histology study. In a third experiment, the total gemcitabine uptake was found to be significantly lower in treated tumors, as assessed in a separate experiment using ex vivo fluorine nuclear magnetic resonance spectroscopy. The amount of active metabolite gemcitabine triphosphate was also lower in treated tumors. In conclusion, the blood flow shutdown induced by VDAs can impact negatively on the delivery of small cytotoxic agents in tumors. The present study outlines the importance of monitoring the tumor vascular function when designing drug combinations.

The goals of cancer therapy are easy to summarize: to identify patients at the earliest stage possible of the disease and to eradicate tumors without altering the overall health condition of the patients. The identification of cancer biomark-ers and tumor-selective drugs therefore represent obvious challenges for the next decades. In the genomics and proteomics era, the temptation is thus enormous to claim that the detection of oncogenes or oncoproteins participating in the progres-sion of a given cancer represents the main avenue to diagnose the disease at early stages and to subsequently target these genes or proteins in order to block tumor growth. However, although the last 30 years have been rich in grasping information about genetic features distinguishing cancer cells from normal cells through the identification of oncogenes and tumor suppressor genes (Hahn and Weinberg, 2002), the translation of this information in new drugs is limited to very few examples. Worse yet, old demons of conventional chemotherapy, namely tox-icity and resistance, are now dampening the original enthusiasm (Force et al., 2007; Knight et al., 2010).Imatinib/Gleevec, as an inhibitor of the bcr-abl fusion protein (Druker et al., 2001) and trastuzumab/Herceptin as inhibitor of the human epidermal growth factor receptor 2 (HER2) (Baselga et al., 1998) are two of the very first examples of the development of molecularly targeted therapies. These drugs have represented breakthroughs in the treatment of chronic myelogenous leukemia (CML) and breast cancers, respectively. The identification of patients who may benefit from these treatments was guided by the detection of corresponding genetic alterations: the Philadelphia chromosome consistently found in CML patients, formed by a recip-rocal translocation of DNA leading to a fusion gene between cABL (chromosome 9) and BCR (chromosome 22) (Bartram et al., 1983), and the overexpression of HER-2/neu as observed in 20–25% inva-sive breast cancers (Slamon et al., 1987). No doubt that these drugs administered to the right population of patients have increased response rates and survival. Still, we know today that the disease can find a way to advance despite the treatments: patients with BCR-ABL or HER2-positive cancers can still progress after receiving the above targeting drugs (often despite encourag-ing first responses). Potential mechanisms of resistance to oncogene-targeting drugs include bypass mechanisms and mutations of the targets (Gorre et al., 2001; Jones and Buzdar, 2009). In addition, potentially fatal cardiac toxicity is reported with trastuzu-mab (Telli et al., 2007) and although better tolerated, hematological (neutropenia), and non-hematological (skin rashes, edema, muscle cramps) toxicities are reported with imatinib (Deininger et al., 2005).The responses to these frustrating obser-vations may be of two kinds. The obvi-ous one is to understand the reasons for the heterogeneity in responses to a given drug, i.e., between patients but also for a given patient, between the early beneficial phases of a treatment and the late devel-opment of resistance. This should lead to rapid results with the apparition of second and third generations of drugs. Some are already making their way to the clinics. Drugs such as nilotinib and so-called ABL allosteric inhibitors may now for instance overcome resistance caused by some BCR-ABL mutations responsible for relapse after initial imatinib treatment (Weisberg et al., 2007; Zhang et al., 2010). This better under-standing should also stimulate the search for new predictive biomarkers to tailor the treatment to a patient’s individual genetic profile (for review, see Hanash et al., 2008; Sawyers, 2008). The need in this matter is so acute that there is an increasing consen-sus to integrate promising biomarkers, even if not clinically qualified, into early phase trials as exploratory and intermediary end-points (Yap et al., 2010).The second and non-exclusive option to tackle the limited amounts of safe and effi-cient drugs issued from our genetic knowl-edge of cancers is to identify additional filter(s) which should be implemented to select for better anticancer drugs. It is now clear that