Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.

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Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.

The origin of cancer

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET) Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2–4 However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models By contrast, cancer cells showed the highest uptake of glutamine This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME Positron emission tomography measurements of nutrient uptake in cells of the tumour microenvironment reveal cell-intrinsic partitioning in which glucose uptake is higher in myeloid cells, whereas glutamine is preferentially acquired by cancer cells

Cell-programmed nutrient partitioning in the tumour microenvironment

Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support malignancy in a non-cell-autonomous way. Two central stromal signaling molecules-TGF-β and SDF1-play a critical role. In early-stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications.

The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy

Hepatocellular carcinoma (HCC) is the most commonmalignancy. Exsome plays a significant role in the elucidation of signal transduction pathways between hepatoma cells, angiogenesis and early diagnosis of HCC. Exosomes are small vesicular structures that mediate interaction between different types of cells, and contain a variety of components (including DNA, RNA, and proteins). Numerous studies have shown that these substances in exosomes are involved in growth, metastasis and angiogenesis in liver cancer, and then inhibited the growth of liver cancer by blocking the signaling pathway of liver cancer cells. In addition, the exosomal substances could also be used as markers for screening early liver cancer. In this review, we summarized to reveal the significance of exosomes in the occurrence, development, diagnosis and treatment of HCC, which in turn might help us to further elucidate the mechanism of exosomes in HCC, and promote the use of exosomes in the clinical diagnosis and treatment of HCC.

/pdf/the-significance-of-exosomes-in-the-development-and-3krbk9hewu.pdf

The significance of exosomes in the development and treatment of hepatocellular carcinoma

We hypothesized that sorafenib plus transarterial chemoembolization (TACE) would confer survival benefits over sorafenib alone for advanced hepatocellular carcinoma (aHCC). We investigated this while using the population-based All-Cancer Dataset to assemble a cohort (n = 3674; median age, 60; 83% men) of patients receiving sorafenib for aHCC (Child-Pugh A) with macro-vascular invasion or nodal/distant metastases. The patients were classified into the sorafenib-TACE group (n = 426) or the propensity score-matched sorafenib-alone group (n = 1686). All of the participants were followed up until death or the end of the study. Time-dependent Cox model and the Mantel–Byar test were used for survival analysis. During the median follow-ups of 221 and 133 days for the sorafenib-TACE and sorafenib-alone groups, 164 (39%) and 916 (54%) deaths occurred, respectively; the corresponding median overall survivals (OS) were 381 and 204 days, respectively (hazard ratio, HR: 0.74; 95% confidence interval, CI, 0.63–0.88; p = 0.021). The one-year and six-month OS were 53.5% and 80.3% in the sorafenib-TACE group and 32.4% and 54.4% in the sorafenib-alone group, respectively. The major complications were comparable between the two groups. The addition of TACE to sorafenib improves survival, with a 26% reduction in mortality. These findings provide strong real-world evidence that supports this combination strategy for eligible Child-Pugh A aHCC patients.

https://www.mdpi.com/2072-6694/11/7/985/pdf

Sorafenib with Transarterial Chemoembolization Achieves Improved Survival vs. Sorafenib Alone in Advanced Hepatocellular Carcinoma: A Nationwide Population-Based Cohort Study.

In 2018, Schneider and Zouboulis analysed the available tools for studying sebaceous gland pathophysiology in vitro. Since then, the interest in this field remains unbroken, as demonstrated by recent reviews on sebaceous gland physiology, endocrinology and neurobiology, the role of sebaceous glands beyond acne, and several original works on different areas of sebaceous gland function, including sebaceous lipogenesis. Landmark developments in the first part of the 30-year modelling research dedicated to the sebaceous gland, which is considered by several scientists as the brain of the skin, were the short-term culture of human sebaceous glands, the culture of human sebaceous gland cells and the development of immortalized sebaceous gland cell lines exhibiting characteristics of normal sebocytes. On the other hand, current developments represent the establishment of sebaceous gland spheroids, the 3D-SeboSkin model of viable skin explants ex vivo, the combination of culture-expanded epidermal stem cells of mice and adult humans to form de novo hair follicles and sebaceous glands, when they are transplanted into excisional wounds in mice, and 3D-printed scaffolds coated with decellularized matrix of adipose-derived mesenchymal stromal cells and SZ95 sebocytes. These novel tools may become useful platforms for better understanding of cellular and molecular mechanisms governing sebocyte biology and sebaceous gland homeostasis, such as the changes in sebum synthesis and composition, the infundibular differentiation and the influence of the innate immunity and the cutaneous microbiome and for identifying potential therapeutic targets of skin diseases affecting the sebaceous glands.

Sebaceous gland: Milestones of 30 years modeling research dedicated to the “brain of the skin”

There is a growing body of evidence that metabolic reprogramming contributes to the acquisition and maintenance of robustness associated with malignancy. The fine regulation of expression levels of amino acid and monocarboxylate transporters enables cancer cells to exhibit the metabolic reprogramming that is responsible for therapeutic resistance. Amino acid transporters characterized by xCT (SLC7A11), ASCT2 (SLC1A5), and LAT1 (SLC7A5) function in the uptake and export of amino acids such as cystine and glutamine, thereby regulating glutathione synthesis, autophagy, and glutaminolysis. CD44 variant, a cancer stem-like cell marker, stabilizes the xCT antiporter at the cellular membrane, and tumor cells positive for xCT and/or ASCT2 are susceptible to sulfasalazine, a system Xc(-) inhibitor. Inhibiting the interaction between LAT1 and CD98 heavy chain prevents activation of the mammalian target of rapamycin (mTOR) complex 1 by glutamine and leucine. mTOR signaling regulated by LAT1 is a sensor of dynamic alterations in the nutrient tumor microenvironment. LAT1 is overexpressed in various malignancies and positively correlated with poor clinical outcome. Metabolic reprogramming of glutamine occurs often in cancer cells and manifests as ASCT2-mediated glutamine addiction. Monocarboxylate transporters (MCTs) mediate metabolic symbiosis, by which lactate in cancer cells under hypoxia is exported through MCT4 and imported by MCT1 in less hypoxic regions, where it is used as an oxidative metabolite. Differential expression patterns of transporters cause functional intratumoral heterogeneity leading to the therapeutic resistance. Therefore, metabolic reprogramming based on these transporters may be a promising therapeutic target. This review highlights the pathological function and therapeutic targets of transporters including xCT, ASCT2, LAT1, and MCT.

https://www.mdpi.com/2218-1989/11/1/27/pdf

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells.

The interplay between apoptosis and ferroptosis mediated by ER stress

Dear Editor, I read with great interest the work of Omoruyi et al. [1], in which the authors showed that a derivative of the antipsychotic drug phenothiazine (DS00329) induced apoptosis in parallel with autophagy. DS00329 treatment led to glioblastoma multiforme (GBM) cells arresting in the G1 phase of the cell cycle partly depending on the cyclin-dependent kinase (CDK) inhibitor p21. Cleaved caspase 3/9 activated poly (ADP-ribose) polymerase (PARP) after the treatment with a PTZ synthesized derivative, which led to the promotion of apoptotic cell death [1]. Several investigations have revealed the therapeutic effectiveness of drug re-positioning for the treatment of brain tumors [1–4]. For instance, it has been identified that the novel therapeutic strategy targeting autophagy in GBM focuses on endogenous neurotransmitters in the synapse as well as conventional drugs [2]. Indeed, Dolma et al. performed the chemical screening of as many as 680 neurochemical compounds using patient-derived GBM neural stem cells (GNS) and the subsequent identification of dopamine receptor D4 (DRD4) antagonists as selective inhibitors of GNS proliferation and inducers of normal neural stem cell differentiation and LC-3 puncta formation [2]. In vivo experiments revealed that a DRD4 antagonist acted synergistically with temozolomide (TMZ) to activate autophagy and inhibited GNS proliferation. DRD4 antagonists suppressed the platelet-derived growth factor (PDGF) receptor-β/ERK1/2 (p44/p42-MAPK) signaling axis and disrupted autophagy flux in GBM cancer stem cells, leading to apoptosis via caspase-3-mediated cleavage of PARP [2]. Furthermore, the purinergic receptor P2Y12 inhibitor ticlopidine, which is an anticoagulant drug widely used to prevent transient ischemic attacks (TIA) and stroke, increased intracellular cAMP levels in low-grade glioma and high-grade astrocytoma and promotes autophagic flux [3]. Notably, tricyclic antidepressants such as imipramine acted synergistically with ticlopidine to promote autophagy in glioma cells by further increasing intracellular cAMP concentrations. In Fig. 6d, the authors showed that LC-3 conversion was promoted in time-dependent manner by the treatment with DS00329 [1]. However, considering the possibility that autophagic flux can be impaired by this derivative of the antipsychotic drug, they should perform Western blot analysis of p62/SQSTM1, the major substrate of selective autophagy. Whereas downregulation of p62/SQSTM1 indicates that Atg5/7-dependent autophagy was really activated, upregulation of p62/SQSTM1 suggests the impaired autophagic flux (i.e. the inhibition of the autophagosome formation). In Fig. 6a, the authors also stained acidic vesicular organelles (AVO) to conclude that OS00329 increased the number of AVO with the activated autophagy [1]. However, it seems to be quite difficult to distinguish autophagolysosomes (the fusion of autophagosomes and lysosomes) from intact lysosomes just by staining AVO. In contrast to the report by Omoruyi et al. [1], which demonstrated that both apoptotic cell death and autophagic flux are activated in the presence of DS00329, it is widely accepted that disruption of the autophagy-lysosome pathway induces apoptosis mainly mediated by excessive endoplasmic reticulum (ER) stress [4]. TMZ is an alkylating agent which induces the formation of O6-methylguanine in DNA strands, which in turn induces mismatch pair with thymine during the following cycle of DNA replication. Genome stress due to TMZ synergistically induces apoptosis in collaboration with accumulated ER stress in response to chloroquine (CQ) treatment [4]. Given the simultaneous activation of both autophagy and apoptosis [1], there is a possibility that DS00329 caused autophagic cell death (ACD). ACD was originally defined as * Go J. Yoshida go-yoshida@juntendo.ac.jp

Go J. Yoshida

Papers

Sorafenib with Transarterial Chemoembolization Achieves Improved Survival vs. Sorafenib Alone in Advanced Hepatocellular Carcinoma: A Nationwide Population-Based Cohort Study.

Sebaceous gland: Milestones of 30 years modeling research dedicated to the “brain of the skin”

The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells.

The interplay between apoptosis and ferroptosis mediated by ER stress

The therapeutic strategy of drug re-positioning to induce autophagic cell death in brain malignancy.