Malignant transformation of cells leads to enhanced glucose uptake and the conversion of a larger fraction of pyruvate into lactate, even under normoxic conditions; this phenomenon of aerobic glycolysis is largely known as the Warburg effect. This metabolic reprograming serves to generate biosynthetic precursors, thus facilitating the survival of rapidly proliferating malignant cells. Extracellular lactate directs the metabolic reprograming of tumor cells, thereby serving as an additional selective pressure. Besides tumor cells, stromal cells are another source of lactate production in the tumor microenvironment, whose role in both tumor growth and the antitumor immune response is the subject of intense research. In this review, we provide an integral perspective of the relationship between lactate and the overall tumor microenvironment, from lactate structure to metabolic pathways for its synthesis, receptors, signaling pathways, lactate-producing cells, lactate-responding cells, and how all contribute to the tumor outcome. We discuss the role of lactate as an immunosuppressor molecule that contributes to tumor evasion and we explore the possibility of targeting lactate metabolism for cancer treatment, as well as of using lactate as a prognostic biomarker.

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In addition to their role in providing cellular energy, mitochondria fulfill a key function in cellular calcium management. The present review provides an integrative view of cellular and mitochondrial calcium homeostasis, and discusses how calcium regulates mitochondrial dynamics and functionality, thus affecting various cellular processes. Calcium crosstalk exists in the domain created between the endoplasmic reticulum and mitochondria, which is known as the mitochondria-associated membrane (MAM), and controls cellular homeostasis. Calcium signaling participates in numerous biochemical and cellular processes, where calcium concentration, temporality and durability are part of a regulated, finely tuned interplay in non-transformed cells. In addition, cancer cells modify their MAMs, which consequently affects calcium homeostasis to support mesenchymal transformation, migration, invasiveness, metastasis and autophagy. Alterations in calcium homeostasis may also support resistance to apoptosis, which is a serious problem facing current chemotherapeutic treatments. Notably, mitochondrial dynamics are also affected by mitochondrial calcium concentration to promote cancer survival responses. Dysregulated levels of mitochondrial calcium, alongside other signals, promote mitoflash generation in tumor cells, and an increased frequency of mitoflashes may induce epithelial-to-mesenchymal transition. Therefore, cancer cells remodel their calcium balance through numerous mechanisms that support their survival and growth. Mitochondrial calcium homeostasisMitochondrial calcium homeostasis is regulated through a fine-tuned process that defines the capacity of the mitochondria

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Despite the recent advances in chemotherapeutic treatments against cancer, some types of highly aggressive and invasive cancer develop drug resistance against conventional therapies, which continues to be a major problem in the fight against cancer. In recent years, studies of alterations of DNA methylome have given us a better understanding of the role of DNA methylation in the development of tumors. DNA methylation (DNAm) is an epigenetic change that promotes the covalent transfer of methyl groups to DNA. This process suppresses gene expression through the modulation of the transcription machinery access to the chromatin or through the recruitment of methyl binding proteins. DNAm is regulated mainly by DNA methyltransferases. Aberrant DNAm contributes to tumor progression, metastasis, and resistance to current anti-tumoral therapies. Aberrant DNAm may occur through hypermethylation in the promoter regions of tumor suppressor genes, which leads to their silencing, while hypomethylation in the promoter regions of oncogenes can activate them. In this review, we discuss the impact of dysregulated methylation in certain genes, which impact signaling pathways associated with apoptosis avoidance, metastasis, and resistance to therapy. The analysis of methylome has revealed patterns of global methylation, which regulate important signaling pathways involved in therapy resistance in different cancer types, such as breast, colon, and lung cancer, among other solid tumors. This analysis has provided gene-expression signatures of methylated region-specific DNA that can be used to predict the treatment outcome in response to anti-cancer therapy. Additionally, changes in cancer methylome have been associated with the acquisition of drug resistance. We also review treatments with demethylating agents that, in combination with standard therapies, seem to be encouraging, as tumors that are in early stages can be successfully treated. On the other hand, tumors that are in advanced stages can be treated with these combination schemes, which could sensitize tumor cells that are resistant to the therapy. We propose that rational strategies, which combine specific demethylating agents with conventional treatment, may improve overall survival in cancer patients.

Lung cancer is the leading cause of cancer deaths worldwide and one of the most common types of cancers. The limited success of chemotherapy and radiotherapy regimes have highlighted the need to develop new therapies like antitumor immunotherapy. CD8+ T-cells represent a major arm of the cell-mediated anti-tumor response and a promising target for developing T-cell-based immunotherapies against lung cancer. Lung tumors, however, have been considered to possess poor immunogenicity; even so, lung tumor-specific CD8+ T-cell clones can be established that possess cytotoxicity against autologous tumor cells. This paper will focus on the alterations induced in CD8+ T-cells by lung cancer. Although memory CD8+ T-cells infiltrate lung tumors, in both tumor-infiltrating lymphocytes (TILs) and malignant pleural effusions, these cells are dysfunctional and the effector subset is reduced. We propose that chronic presence of lung tumors induces dysfunctions in CD8+ T-cells and sensitizes them to activation-induced cell death, which may be associated with the poor clinical responses observed in immunotherapeutic trials. Getting a deeper knowledge of the evasion mechanisms lung cancer induce in CD8+ T-cells should lead to further understanding of lung cancer biology, overcome tumor evasion mechanisms, and design improved immunotherapeutic treatments for lung cancer.

Calcitriol is a multitarget anticancer hormone; however, its effects on angiogenesis remain contradictory. Herein, we tested whether the antiangiogenic phytochemicals curcumin or resveratrol improved calcitriol antitumorigenic effects in vivo. Triple-negative breast cancer tumoral cells (MBCDF-T) were xenografted in nude mice, maintaining treatments for 3 weeks. Tumor onset, volume and microvessel density were significantly reduced in mice coadministered with calcitriol and curcumin (Cal+Cur). Vessel count was also reduced in mice simultaneously treated with calcitriol and resveratrol (Cal+Rsv). Cal+Cur and Cal+Rsv treatments resulted in less tumor activated endothelium, as demonstrated by decreased tumor uptake of integrin-targeted biosensors in vivo. The renal gene expression of Cyp24a1 and Cyp27b1 suggested increased calcitriol bioactivity in the combined regimens. In vitro, the phytochemicals inhibited both MBCDF-T and endothelial cells proliferation, while potentiated calcitriol’s ability to reduce MBCDF-T cell-growth and endothelial cells migration. Resveratrol induced endothelial cell death, as deduced by increased sub-G1 cells accumulation, explaining the reduced tumor vessel number in resveratrol-treated mice, which further diminished when combined with calcitriol. In conclusion, the concomitant administration of calcitriol with curcumin or resveratrol synergistically promoted anticancer effects in vitro and in vivo in human mammary tumor cells. Whereas the results suggest different mechanisms of action of the phytochemicals when coadministered with calcitriol, the converging biological effect was inhibition of tumor neoangiogenesis.