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The past few decades have witnessed a major leap in knowledge relating to the role of tumor microenvironment (TME) in carcinogenesis and evolving behavior of the tumor. Multiple factors within the TME modulate the cancer cells and the associated therapies. Stephen Paget first asserted that the microenvironment plays an important role in the growth of tumor metastasis. The most important player in the TME is cancer-associated fibroblast (CAF) which significantly participates in the proliferation, invasion, and metastasis of tumor cells. CAFs show phenotypic and functional heterogeneity. Mostly CAFs originate from quiescent resident fibroblast or mesoderm-derived precursor cells (mesenchymal stem cells), although several alternate sources of origin have been noted. However, due to lack of specific fibroblast-restricted markers, it is very difficult to trace lineage and identify the biological origin of distinct subtypes of CAFs. CAFs are predominantly shown by several studies to mainly act as tumor-promoting agents, however, tumor-inhibiting actions are also being validated by several studies. A more objectified and comprehensive functional and phenotypic classification of CAF is required, which will help in better way for tumor management. Here, in this review, we have tried to review the current status of CAF origin, along with phenotypic and functional heterogeneity, and recent progress in CAF research., (© 2023 International Federation for Cell Biology.)

Malignantly transformed cells must alter their metabolic status to stay viable in a harsh microenvironment and maintain their ability to invade and spread. Anoikis, a specific detachment-related form of apoptotic cell death, is a potential barrier to cancer cell metastasis. Several molecular/pathway alterations have been implicated in preventing anoikis in metastatic cancers. Specific alterations in the lipid metabolism machinery (such as an increase in fatty acid uptake and synthesis) and modifications in the carbohydrate and amino acid metabolism are partially identified mechanisms associated with the anoikis resistance in various types of cancers, among other survival benefits. Following a summary of the molecular basis of the anoikis pathway, its resistance mechanisms, and the fundamentals of lipid metabolism in cancer, this article aims to elucidate the impact of lipid metabolism deviations recruited by cancer cells to escape anoikis., (© 2022 International Federation for Cell Biology.)

The efficacy of cisplatin-based chemotherapy in malignancy is limited by the occurrence of innate and acquired drug resistance. Clinical observations suggest that targeting phytopharmaceuticals is the right choice to enhance the effectiveness of conventional chemotherapy. We aimed to evaluate the effects of diosgenin (DG) combined with cisplatin on apoptosis and its underlying mechanisms in the A549 non-small cell lung cells. Cell viability was measured using an MTT assay. Western blot was used for the measurement of γ-H2AX and 8-Hydroxy-2'-deoxyguanosine expression level. DCFH-DA fluorescence dye was used to detect reactive oxygen species (ROS) in cells. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase were also assessed. For evaluation of apoptosis, TUNEL assay was used. DG significantly increases the cytotoxic effects of cisplatin. Besides, DG considerably increased the expression levels of γ-H2AX in cells. Upon melatonin treatment, ROS levels were increased, and antioxidant enzymes expression levels were significantly decreased. Co-treatment of DG and cisplatin resulted in increased cellular cytotoxicity through increasing ROS levels, inducing oxidative DNA damage, and decreasing cellular antioxidant defense, hence led to potent induction of apoptosis in tumor cells., (© 2022 International Federation for Cell Biology.)

The incidence of gliomas is increasing. Although great progress in glioma treatment has been made, the clinical outcome remains unsatisfactory. Chemokine (C-C motif) ligand 2 (CCL2) plays a key role in different types of cancers, including glioma. However, the function of CCL2 in glioma chemoresistance is not fully understood. In the current study, CCL2 was significantly upregulated in glioma. More importantly, CCL2 and CCR2 were significantly upregulated in temozolomide (TMZ)-resistant glioma. TMZ-resistant malignant glioblastoma cells (U251/TMZ) had higher expressions of CCL2 and CCR2 and a higher level of glycolysis as compared to its parental cell line U251. Silencing of CCL2 in U251/TMZ cells inhibited glycolysis. Overexpression of CCL2 reduced TMZ-induced apoptosis through activation of the AKT pathway and promotion of glycolysis. Moreover, overexpression of CCL2 significantly reduced the antitumor effect of TMZ in vivo. In conclusion, CCL2 overexpression reduced the antitumor effect of TMZ by enhancing glycolysis through activation of AKT signaling. The findings highlighted the importance of CCL2/CCR2/glycolysis and its potential value in developing new treatment for glioma., (© 2022 International Federation for Cell Biology.)

Nucleotide-binding oligomerization domain-like receptors (NLRs) are crucial types of innate immune sensors and well known for their critical roles in the immune system. However, how NLRP2 functions in the progression of cancer is largely unknown. Here, we identified NLRP2 as an antioncogene in lung adenocarcinoma (LUAD) cells. Gain- and loss-of-function studies revealed that NLRP2 silencing promoted cell proliferation and migration by stimulating NF-kB signaling in the microenvironment, which induced epithelial-to-mesenchymal transition (EMT) phenotype and cytoskeleton reorganization in LUAD cells. The addition of the NF-kB inhibitor rescued the function of NLRP2 on EMT. Moreover, NLRP2 increased the level of cofilin phosphorylation and repressed subsequent F-actin reorganization. Consistently, the in vivo study showed that NLRP2 played an inhibitory role in forming metastasis foci. Taken together, NLRP2 inhibited cell proliferation and migration by regulating EMT in LUAD cells, demonstrating the essential function of NLRP2 in the development of LUAD., (© 2021 International Federation for Cell Biology.)

Although the identification of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of many cancer types including chronic myeloid leukemia (CML), still adjustment of neoplastic cells to cytotoxic effects of anticancer drugs is a serious challenge. In the area of drug resistance, epigenetic alterations are at the center of attention and the present study aimed to evaluate whether blockage of epigenetics mechanisms using a pan-histone deacetylase (HDAC) inhibitor induces cell death in CML-derived K562 cells. We found that the abrogation of HDACs using panobinostat resulted in a reduction in survival of the K562 cell line through p27-mediated cell cycle arrest. Noteworthy, the results of the synergistic experiments revealed that HDAC suppression could be recruited as a way to potentiate cytotoxicity of Imatinib and to enhance the therapeutic efficacy of CML. Here, we proposed for the first time that the inhibitory effect of panobinostat was overshadowed, at least partially, through the aberrant activation of the phosphoinositide 3-kinase (PI3K)/c-Myc axis. Meanwhile, we found that upon blockage of autophagy and the proteasome pathway, as the main axis involved in the activation of autophagy, the anti-leukemic property of the HDAC inhibitor was potentiated. Taken together, our study suggests the beneficial application of HDAC inhibition in the treatment strategies of CML; however, further in vivo studies are needed to determine the efficacy of this inhibitor, either as a single agent or in combination with small molecule inhibitors of PI3K and/or c-Myc in this malignancy., (© 2021 International Federation for Cell Biology.)