Hypoxia dictates metabolic rewiring of tumors: implications for chemoresistance

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

Targeting hif-1α regulatory pathways as a strategy to hamper tumor-microenvironment interactions in cll

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor-and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells

Targeting hif-1α regulatory pathways as a strategy to hamper tumor-microenvironment interactions in cll

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells

Endothelial heme dynamics drive cancer cell metabolism by shaping the tumor microenvironment

The crosstalk among cancer cells (CCs) and stromal cells within the tumor microenvironment (TME) has a prominent role in cancer progression. The significance of endothelial cells (ECs) in this scenario relies on multiple vascular functions. By forming new blood vessels, ECs support tumor growth. In addition to their angiogenic properties, tumor-associated ECs (TECs) establish a unique vascular niche that actively modulates cancer development by shuttling a selected pattern of factors and metabolites to the CC. The profile of secreted metabolites is strictly dependent on the metabolic status of the cell, which is markedly perturbed in TECs. Recent evidence highlights the involvement of heme metabolism in the regulation of energy metabolism in TECs. The present study shows that interfering with endothelial heme metabolism by targeting the cell membrane heme exporter Feline Leukemia Virus subgroup C Receptor 1a (FLVCR1a) in TECs, resulted in enhanced fatty acid oxidation (FAO). Moreover, FAO-derived acetyl-CoA was partly consumed through ketogenesis, resulting in ketone bodies (KBs) accumulation in FLVCR1a-deficient TECs. Finally, the results from this study also demonstrate that TECs-derived KBs can be secreted in the extracellular environment, inducing a metabolic rewiring in the CC. Taken together, these data may contribute to finding new metabolic vulnerabilities for cancer therapy

Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands

Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum­(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure–activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum­(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment

Language Usage Conditions of Multilingual Nations - Sri Lanka“Sinhalese native speakers and Tamil native speakers\u27 scenes, their word usage conditions in Western Province and Uva Province .

Sri Lanka is a multilingual nation, where various languages, races, and religions exist. Sinhalese, Muslims and Tamils reside together with Burger, Marais and native people called ‘Veddah\u27. Sri Lankan people use three languages; Sinhala, English, and Tamil in their daily communication. To examine the language situation in Sri Lanka means to analyze the cultural and social circumstances within Sri Lanka.In particular the Code Switching (CS) is seen in various situations in Sri Lanka. It is expected that a person would switch the language code depending on the situation. This also differs according to various circumstances such as speaker\u27s life style and living conditions at home, academic background and the social hierarchy. Furthermore, it is estimated that differences in CS between Tamil minority and Sinhala majority would exist. It is important to consider these points in order to examine the situation of communication. English is also used quite often in Sri Lanka. The influence and the necessity of English would be examined through a survey of English usage spreading in the real world.The questionnaire style survey has been conducted and it was administered based on pilot research in Japan. It is necessary to investigate various circumstances that people face in order to examine the true language usage conditions. The investigation considered people in various places and situations throughout Sri Lanka.Sri Lanka consists of nine states. The research was done in eight states: Central Province, Eastern Province, Northern Province, Southern Province, Western Province North western Province, Uva Province and Sabaragamuwa province.The research was done as follows:The locations : at a house of a standard family, at a bank, at a school and at a postoffice in each locations.The subjects : 525 people including students, office workers, house-wives, farmers,and elderly people.The format of investigation: The questionnaire included four communication situations and questionsIn this paper, the language usage conditions of Sinhalese native speakers and the Tamil native speakers of both Western Province and Uva Province are analyzed in various situations. As the result, the Sinhalese native speakers in Western Province showed many examples of code switching between Sinhalese and English. Moreover, English code switching was seen frequently in the home.When considering the Uva Province, the Sinhalese native speakers use both Sinhala and English while a significant proportion of them are trilingual speakers there. They often change between the three main languages; Sinhala, English and Tamil are used quite often at schools, offices, hospitals, and so on.To examine a number of communication scenes in different language groups in Sri Lanka, it was clearly seen that there are more trilingual speakers among Tamil native speakers who more likely to switch between three languages in different situations, while Sinhalese speakers switch between two languages. The data of the survey also showed that the usage of languages varies according to the speakers\u27 social status, region where he or she lives, academic background, age, etc.Moreover, when the communication is taking place at home, the Sinhalese native speakers often use the code switching between Sinhalese and English. However, the elderly people in Sri Lanka, especially people living in Uva Province, rarely speak English due to their poor academic background.It has become clear that the language usage conditions differ from one another depending on the society, the region, and the educational level, and age of the person in Sri Lanka.However it is not well known yet when and how the code switching happens. As for code switching between English and Sinhalese, it is important to record their natural conversation in various scenes to analyze certain characteristics of the code switching. This would help clarify how Sri Lankans use these languages.千葉大学大学院人文社会科学研究科研究プロジェクト報告書第239集「ユーラシアの多言語社会と言語政策」中川裕 編Eurasian Multilingual Society and Language Policy Report on Research Project No.23