Affect Cancer Progression Research Articles

An Immune-Related Gene Signature Can Predict Clinical Outcomes and Immunotherapeutic Response in Oral Squamous Cell Carcinoma.

Objective: Immune landscape is a key feature that affects cancer progression, survival, and treatment response. Herein, this study sought to comprehensively characterize the immune-related genes (IRGs) in oral squamous cell carcinoma (OSCC) and conduct an immune-related risk score (IRS) model for prognosis and therapeutic response prediction. Methods: Transcriptome profiles and follow-up data of OSCC cohorts were curated from TCGA, GSE41613, and IMvigor210 datasets. An IRS model was established through univariate Cox, Random Survival Forest, and multivariate Cox analyses. Prognostic significance was evaluated with Kaplan–Meier curves, ROC, uni- and multivariate Cox, and subgroup analyses. A nomogram was conducted and assessed with C-index, ROC, calibration curves, and decision curve analyses. Immune cell infiltration and immune response were estimated with ESTIMATE and ssGSEA methods. Results: An IRS model was constructed for predicting the overall survival and disease-free survival of OSCC, containing MASP1, HBEGF, CCL22, CTSG, LBP, and PLAU. High-risk patients displayed undesirable prognosis, and the predictive efficacy of this model was more accurate than conventional clinicopathological indicators. Multivariate Cox analyses demonstrated that this model was an independent risk factor. The nomogram combining IRS, stage, and age possessed high clinical application values. The IRS was positively associated with a nonflamed tumor microenvironment. Moreover, this signature enabled to predict immunotherapeutic response and sensitivity to chemotherapeutic agents (methotrexate and paclitaxel). Conclusion: Collectively, our study developed a robust IRS model with machine learning method to stratify OSCC patients into subgroups with distinct prognosis and benefits from immunotherapy, which might assist identify biomarkers and targets for immunotherapeutic schemes.

Cancer-associated fibroblasts in the single-cell era.

Cancer-associated fibroblasts (CAFs) are central players in the microenvironment of solid tumors, affecting cancer progression and metastasis. CAFs have diverse phenotypes, origins and functions and consist of distinct subpopulations. Recent progress in single-cell RNA-sequencing technologies has enabled detailed characterization of the complexity and heterogeneity of CAF subpopulations in multiple tumor types. In this Review, we discuss the current understanding of CAF subsets and functions as elucidated by single-cell technologies, their functional plasticity, and their emergent shared and organ-specific features that could potentially be harnessed to design better therapeutic strategies for cancer.

Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors

Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4 + or CD8 + T cells. The MCMV CD8 + T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4 + T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen–specific CD8 + T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8 + T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8 + T cell–peptide epitopes alone or CD4 + T cell–peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen–agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.

Abstract 3187: Understanding the role of cancer-associated fibroblasts (CAFs) on pathogenesis of KRAS mutated cancers by defining differences in the basal state proteome and secretome

Abstract Background: KRAS is commonly mutated in solid tumors. Cancer-associated fibroblasts (CAFs) are a key tumor stroma component, which can affect cancer progression and drug response. We hypothesized that defining the differential secreted proteins between CAFs and KRAS mutant-cancer cells could reveal potential mechanisms by which CAFs influence cancer progression and drug resistance. Methods: We studied 12 cell lines: 3 KRAS mutant-colorectal cancer cell lines (H747, LIM2099 and SW620), 3 KRAS mutant-lung cancer cell lines (H1792, H2030 and H23), 3 KRAS mutant-pancreatic cancer cell lines (CAPAN1, DANG, MIAPACA2) and 3 CAF cell line models (colorectal and lung CAF and pancreatic stellate cells). We quantified proteins in cell lines and serum-free media after 24 hour incubation in cells using mass spectrometry in a multiplexed manner (12plex) in triplicates to characterize the proteome and the profile of secreted proteins (secretome), respectively. Prediction software (signalP, secretomeP, TMHMM) and databases (surfaceome and cell surface protein atlas) were used to annotate secreted or transmembrane proteins. Results: Our proteome analysis quantified 9307 proteins. T-test between the cell types (CAF vs cancer) identified 1770 differentially expressed proteins, where 712 proteins were CAF-enriched. This included known CAF markers (e.g α smooth muscle actin) but also proteins not known to be CAF markers such as heat shock protein beta-5/6 (HSPB5/6). The secretome analysis identified 2330 secreted or transmembrane proteins where 202 were differentially expressed between cancer cells and CAFs. 190 proteins were CAF-enriched with the highest ranking being syndecan-2 (SDC2), collagen α-28(I) chain (COL28A1), decorin (DCN) and wnt family member 5B (WNT5B). Interestingly, basal proteome analysis of KRAS mutant-cancer cells showed expression of receptors corresponding to the CAF-enriched ligands, such as receptor tyrosine kinase-like orphan receptor 1/2 (ROR1/2) which respond to WNT5B. This suggests that CAF-enriched ligands may activate certain downstream pathways, including non-canonical WNT signaling, in KRAS mutant-cancer cells. Conclusion: We undertook deep quantitative proteomics where we identified potential novel CAF markers HSPB5/6. We have also found proteins in the CAF secretome, such as WNT5B, which may drive drug resistance in KRAS mutant-cancer cells. Citation Format: Rachel Lau, Lu Yu, Theodoros Roumeliotis, Lisa Pickard, Adam Stewart, Jyoti Choudhary, Udai Banerji. Understanding the role of cancer-associated fibroblasts (CAFs) on pathogenesis of KRAS mutated cancers by defining differences in the basal state proteome and secretome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3187.

Abstract 1574: LSD-germline variant drive oncogenicity

Abstract Lysosome storage disease (LSD) is a congenital metabolic disorder caused by mutations in genes involved in the function of lysosomes. Defects in the genes encoding hydrolases and transporters and enzyme activators are found in LSD’s, leading to the accumulation of macromolecules in the late endocytic system. And this disruption of lysosomal homeostasis increases the induction of endoplasmic reticulum and oxidative stress, proliferative signal transduction, extracellular matrix degradation, Integrin-β4-mediated cell migration and invasion, and consequently can promote the development of oncogenic cells and malignant tumors. It is known that the function of lysosomes is very important in cancer diseases. Recently, through a preliminary study, we found that the incidence of myeloproliferative neoplasm (MPN) increases statistically significantly when the LSD putative pathogenic germline variant (PPGV) is present. Based on this, we performed single-cell RNA (scRNA) sequencing using MPN patient samples of both LSD PPGV carrier and non-carrier. We tried to determine how the LSD PPGV affects MPN cancer progression at the single-cell level. To confirm functional differences between the two groups, DEG, pathway enrichment, LR-pair interaction, and transcription enrichment analyses were performed. In the analysis, immune cells were composed of T-cell, NK-cell, and Monocyte (in the order of frequency). It was confirmed that Lysosome-related (ER, Golgi, etc.) functions were upregulated in the carrier group compared to the non-carrier group across cell types. In addition, in the ligand-receptor (LR)-pair interaction analysis targeting Immune cells, it was possible to find a statistically significant difference (average log2 fold change>0.7 and p-value<0.05) candidate LR-pair (IL6-IL6R*IL6ST) that upregulates in the carrier group compared to the non-carrier group. The candidate LR-pair found by our team has been previously known as a cytokine-related gene that plays an inflammatory or fibrosis-related role in MPN and affects cancer progression. Also, in the Transcription Factor Enrichment analysis conducted together, it was confirmed that the statistically significant (NES>2 and FDR<0.01) candidate Transcription Factor (STAT1), which operates dependent on the candidate LR-pair, is upregulated. In conclusion, we found the possibility that genes and functions related to cancer progression can be up-regulated by LSD germline variants. In addition, we plan to conduct additional studies to determine the exact mechanism of contribution to cancer development by the LSD germline variant. Citation Format: Hyundong Yoon, Seulki Song, Yeeun Ha, Youngil Koh, SungSoo Yoon. LSD-germline variant drive oncogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1574.

Lactate dehydrogenase as a surrogate marker for both PCR and survival in breast cancer patients who underwent neoadjuvant chemotherapy.

e12621 Background: Glucose metabolism in cancer cells produces various glycolytic metabolites, which can affect cancer progression and treatment outcome. Herein we evaluated the association of glucose transporters and enzymes involved in glucose metabolism with clinic-pathological factors and outcomes in breast cancer patients who underwent neoadjuvant chemotherapy(NAC). Methods: We selected 7 target transporters and enzymes(GLUT1, hexokinase 2, lactate dehydrogenase, MCT1, MCT4, IGF1RA, and IGF1RB) involved in glucose metabolism. Their tumoral expressions were scored both quantitively and qualitatively based on tissue microarrays and immunohistochemistry as previously described (Pinheiro et al, 2010) and then evaluated in relationships with pretreatment clinical/pathological characteristics and treatment outcomes including findings of 18F-FDG PET/CT,pathologic complete response(pCR), and relapse in breast cancer(stage IIA-IIIC) patients who underwent anthracycline or taxane-based NAC. Results: Of the 236 enrolled patients, 145(61.4%), 44(18.6%), and 47(19.9%) were luminal, HER2-enriched, and TNBC subtypes. Pathologic CR was determined 50(21.2%) and 57(24.2%) relapses, 42(17.8%) distant relapses, and 28 deaths were observed during median follow-up duration of 64.0 (32.3-114.9) months. The expression rates of the target molecules were 76.0, 31.1, 42.1, 54.9, 67.9, 78.4, and 49.8% for GLUT1, hexokinase 2 (HK2), lactate dehydrogenase(LD), MCT1, MCT4, IGF1RA, and IGF1RB, respectively. Among target molecules in glucose metabolism, LD was significantly associated with pCR(OR = 0.251; p- = 0.016) and distant disease-free survival (HR = 2.29; P = 0.019). Plus, LD expression shows a trend for a high SUVmax of primary tumor 18F-FDG PET/CT(OR = 1.797 P = 0.060). Conclusions: Tumoral expression of lactate dehydrogenase can be considered as a predictive marker for pCR to NAC and plus prognostic marker for survival in patients with breast cancer.

LncRNAs and CircRNAs in cancer

It is well known that noncoding RNAs (ncRNAs) cannot encode proteins, but they can play important regulatory roles in tumors by combining with proteins, RNAs, and DNAs. As more and more studies reveal the important roles and underlying mechanisms of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in cancer, their huge application potential in cancer therapy cannot be ignored. For example, lncRNAs can be involved in tumor‐related signal transduction pathways, cell cycle control, DNA damage, epigenetic regulation, and microRNA control. A group of studies confirmed that abnormal expression of lncRNAs can affect cancer progression. Furthermore, as covalently closed continuous circular ncRNAs, many recent studies have shown that circRNAs have regulatory effects and other important biological significances in cancer. Interestingly, circRNAs were found to have translational functions. This has greatly attracted people's attention to circRNAs research. In this review, we introduce the important roles of lncRNAs and circRNAs in some representative cancers, respectively. Furthermore, we focus on the biological functions and important clinical therapeutic implications of lnRNAs and circRNAs in neuroblastoma. Our review also focuses on providing rationale and relevant references for novel biomarkers for neuroblastoma diagnosis, prognosis, and treatment.

Early Social Enrichment Modulates Tumor Progression and p53 Expression in Adult Mice.

Epidemiological evidence indicates that stress and aversive psychological conditions can affect cancer progression, while well-being protects against it. Although a large set of studies have addressed the impact of stress on cancer, not much is known about the mechanisms that protect from cancer in healthy psychological conditions. C57BL/6J mouse pups were exposed to an environmental enrichment condition consisting of being raised until weaning by the biological lactating mother plus a non-lactating virgin female (LnL = Lactating and non-Lactating mothers). The Control group consisted of mice raised by a single lactating mother (L = Lactating). Four months after weaning, mice from LnL and L conditions were exposed to intramuscular injection of 3-methylcolantrene (3MCA), a potent tumorigenic drug, and onset and progression of 3MCA-induced fibrosarcomas were monitored over time. Pups from the LnL compared to the L group received more parental care and were more resilient to stressful events during the first week of life. In association, the onset of tumors in LnL adults was significantly delayed. At the molecular level, we observed increased levels of wild-type p53 protein in tumor samples of LnL compared to L adults and higher levels of its target p21 in healthy muscles of LnL mice compared to the L group, supporting the hypothesis of potential involvement of p53 in tumor development. Our study sustains the model that early life care protects against tumor susceptibility.

LINC01535 Attenuates ccRCC Progression through Regulation of the miR-146b-5p/TRIM2 Axis and Inactivation of the PI3K/Akt Pathway.

lncRNAs, a group of eukaryotic cell genome-encoded transcripts, have been demonstrated to exert a notable impact on tumorigenesis. LINC01535, belonging to the lncRNA family, was reported to have an aberrant expression in certain types of cancers and thus affect cancer progression. Nevertheless, the expression pattern and potential roles of LINC01535 in clear cell renal cell carcinoma (ccRCC) remain to be elucidated. Here, LINC01535 expression was detected in ccRCC by RT-qPCR, cell proliferation by CCK-8 assays, and invasion by transwell assays. Besides, effects of LINC01535 on in vivo tumor growth were investigated by xenograft tumor models. The miR-146b-5p/LINC01535/TRIM2 interaction was evaluated via luciferase reporter assays. This study showed downregulation of LINC01535 in ccRCC. Moreover, LINC01535 upregulation attenuated in vitro ccRCC development and hindered in vivo tumor growth. Furthermore, LINC01535 sponged miR-146b-5p which had a negative correlation with LINC01535, and TRIM2 was a direct target of miR-146b-5p and mediated by LINC01535. Mechanically, LINC01535/miR-146b-5p/TRIM2 axis affected ccRCC progression by mediating the PI3K/Akt signaling. All in all, our observations suggest the LINC01535/miR-146b-5p/TRIM2 axis as a crucial role in ccRCC.

Exosomes Regulate the Epithelial-Mesenchymal Transition in Cancer.

Exosomes are important mediators of intercellular communication and participate in complex biological processes by transferring a variety of bioactive molecules between cells. Epithelial–mesenchymal transition (EMT) is a process in which the cell phenotype changes from epithelioid to mesenchymal-like. EMT is also an important process for cancer cells by which they acquire invasive and metastatic capabilities, which aggravates the degree of tumor malignancy. Numerous studies have demonstrated that exosomes encapsulate various components, such as microRNAs and proteins, and transfer information between tumor cells or between tumor cells and the tumor microenvironment, thereby regulating the EMT process. Exosomes can also be used for cancer diagnosis and treatment or as a drug delivery platform. Thus, they can be used as a therapeutic tool to control the occurrence of EMT and affect cancer progression. In this review, we summarize the latest research advancements in the regulation of the EMT process in tumor cells by the contents of exosomes. Furthermore, we discuss the potential and challenges of using exosomes as a tool for cancer treatment.

Sex differences in primary malignant cardiac tumors: A multi-institutional cohort study from National Cancer Database.

Despite the significant clinical importance of sex among factors affecting cancer progression and survival, it remains one of the least studied factors. Therefore, we sought to examine these differences in relation to primary malignant cardiac tumors (PMCTs) using a national data set. The 2004-2017 National Cancer Database was queried for patients with PMCTs. Annual trend of females' percent was assessed. Overall survival predictors were evaluated with Kaplan-Meier and Cox-regression. Subgroup analysis was done based on histology, comorbidity index, race, insurance, and surgical treatment. PMCTs were identified in 736 patients (median age 52, female [47.8%]). Most of them were high-grade (49.2%). About 60% underwent surgery. Angiosarcoma (43%), fibrosarcoma (5.2%), and leiomyosarcoma (5.2%) were the most common pathologies. Based on multivariate Cox-regression, higher income, higher comorbidity index, angiosarcoma, and Stage III/IV were associated with higher late mortality, while year of diagnosis and use of surgery or chemotherapy were associated with lower mortality. Among the surgical group, age, higher income, higher comorbidity index, angiosarcoma, and Stage III/IV were independent predictors of higher late mortality, while private insurance and year of diagnosis were associated with lower late mortality. No difference was seen between males and females in 30-day and late mortality (p = .71). Subgroup analysis based on Cox-regression showed no differences in late mortality between males and females. PMCTs have poor overall survival. Surgery and chemotherapy were associated with longer survival benefits. On the contrary, the associated risk factors for mortality were advanced age, higher comorbidity index, angiosarcoma histology, and Stage III/IV.

A probabilistic data analytics methodology based on Bayesian Belief network for predicting and understanding breast cancer survival

Understanding breast cancer survival has proven to be a challenging problem for practitioners and researchers. Identifying the factors affecting cancer progression, their interrelationships, and their influence on patients’ long-term survival helps make timely treatment decisions. The current study addresses this problem by proposing a Tree-Augmented Bayesian Belief Network (TAN)-based data analytics methodology comprising of four steps: data acquisition and preprocessing, variable selection via Genetic Algorithm (GA), data balancing with synthetic minority over-sampling and random under-sampling methods, and finally the development of the TAN model to determine the probabilistic inter-conditional dependency structure among breast cancer-related variables along with the posterior survival probabilities The proposed model is compared to well-known machine learning models. A what-if analysis has also been conducted to verify the associations among the variables in the TAN model. The relative importance of each variable has been investigated via sensitivity analysis. Finally, a decision support tool is developed to further explore the conditional dependency structure among the cancer-related factors. The results produced by the proposed methodology, namely the patient-specific posterior survival probabilities and the conditional relationships among the variables, can be used by healthcare professionals and physicians to improve the decision-making process in planning and managing breast cancer treatments. Our generic methodology can also accommodate other types of cancer and be applied to manage various medical procedures.

The ALDH Family Contributes to Immunocyte Infiltration, Proliferation and Epithelial-Mesenchymal Transformation in Glioma.

Gliomas are malignant tumors that originate from the central nervous system. The aldehyde dehydrogenase family has been documented to affect cancer progression; however, its role in gliomas remains largely unexplored. Bulk RNA-seq analysis and single-cell RNA-Seq analysis were performed to explore the role of the aldehyde dehydrogenases family in gliomas. Training cohort contained The Cancer Genome Atlas data, while data from Chinese Glioma Genome Atlas and Gene Expression Omnibus were set as validation cohorts. Our scoring system based on the aldehyde dehydrogenases family suggested that high-scoring samples were associated with worse survival outcomes. The enrichment score of pathways were calculated by AUCell to substantiate the biofunction prediction results that the aldehyde dehydrogenases family affected glioma progression by modulating tumor cell proliferation, migration, and immune landscape. Tumor immune landscape was mapped from high-scoring samples. Moreover, ALDH3B1 and ALDH16A1, two main contributors of the scoring system, could affect glioblastoma cell proliferation and migration by inducing cell-cycle arrest and the epithelial-mesenchymal transition. Taken together, the aldehyde dehydrogenases family could play a significant role in the tumor immune landscape and could be used to predict patient prognosis. ALDH3B1 and ALDH16A1 could influence tumor cell proliferation and migration.

CircWHSC1 Promotes Breast Cancer Progression by Regulating the FASN/AMPK/mTOR Axis Through Sponging miR-195-5p.

Numerous studies reveal that circular RNAs (circRNAs) affect cancer progression. CircWHSC1 is a novel circRNA that accelerates ovarian cancer progression. Nevertheless, the function of circWHSC1 in regulating breast cancer (BC) is elusive. Here, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was carried out to detect the profiles of circWHSC1 and miR-195-5p in BC tissues and corresponding non-tumor tissues. Gain- and loss-of-function assays were implemented both in vivo and ex vivo to verify the significance of circWHSC1 in BC development. BC cell proliferation was estimated by the cell counting kit-8 (CCK-8) and BrdU assays. Transwell assay was implemented to test BC cell migration and invasion. The protein levels of FASN, AMPK and mTOR were determined by Western blot. Moreover, immunohistochemistry was performed to examine Ki67 and FASN expression. As shown by the result, circWHSC1 was up-regulated in BC tissues versus adjacent non-tumor tissues. circWHSC1 overexpression was correlated with higher tumor stages, lymphatic metastasis and worse survival of BC patients. Functionally, overexpressing circWHSC1 amplified proliferation, migration and invasion of BC cell lines and boosted xenograft tumor growth in nude mice. Bioinformatics uncovered that circWHSC1 functioned as a competitive endogenous RNA by sponging miR-195-5p, which was further corroborated by the dual-luciferase reporter assay and RNA immunoprecipitation. miR-195-5p delayed BC progression, which was dampened by circWHSC1 up-regulation. Fatty acid synthase (FASN) was affirmed as a direct target of miR-195-5p. miR-195-5p overexpression curbed FASN expression and activated its downstream AMPK pathway. Inhibition of FASN or activation of the AMPK pathway reversed circWHSC1-mediated oncogenic effects. Collectively, CircWHSC1 acted as an oncogene to expedite BC evolvement by modulating the miR-195-5p/FASN/AMPK/mTOR pathway.

The Functional Role of Extracellular Matrix Proteins in Cancer.

Simple SummaryExtracellular matrix is a three-dimensional network of macromolecules that provide structural and biochemical support to surrounding cells. Extracellular matrix plays a critical role in the development and progression of cancer. The extracellular matrix of the tumor is very different from the matrix of the normal tissue. Mainly fibroblasts produce and regulate matrix remodeling, but in cancer, the tumor matrix also originates from cancer cells. We describe the mechanisms of how the protein composition and structure of the extracellular matrix changes during cancer progression and how abnormal matrix deregulates the behavior of stromal cells and influences cancer progression.The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells.

Exosomes and the extracellular matrix: a dynamic interplay in cancer progression.

Exosomes are a subtype of extracellular vesicles (EVs) composed of a lipid bilayer, which carry various cargoes such as nucleic acids, proteins, and bioactive lipids. Cancer cells release exosomes to promote cell communication and interaction with the extracellular matrix (ECM). ECM regulates the secretion and uptake of exosomes. Moreover, the cargo of exosomes can control ECM remodeling, thus affecting cancer progression. Aside from the rearrangement of ECM, exosomal cargo also modulates different signaling pathways that maintain homeostasis and play a major role in tumor growth and immune evasion in the tumor microenvironment (TME). Exosomes are now widely recognized as circulating biomarkers for diagnosis and prognosis. Their role in cancer initiation, progression, and chemoresistance is becoming increasingly clear from preclinical and clinical investigations, thereby gaining interest for their potential use as cancer diagnostics tools, but also for the development of future innovative cancer therapeutics. In this mini review we outline and discuss the correlation between exosomes, TME and cancer progression, while focusing on the potential role of exosomes as diagnostic and prognostic biomarkers, as well as therapeutic vehicles for drug delivery.

The novel function of PMS2 mutation on ovarian cancer proliferation

The PMS2 gene encodes a protein that plays an essential role in repairing DNA. Recent studies have shown that the S815L PMS2 mutation, rarely found in ovarian cancer (3%), causes a reduction in the PMS2 protein’s mismatch repair activity in vitro. However, no studies have focused on how this mutation affects cancer progression. Although occurrences of patients with cancers associated with the PMS2 mutation are rare, the lack of studies published on this mutation still negatively impacts their treatment. Our study aimed to discover the novel effect of this mutation in ovarian cancer cells. We hypothesized that overexpressing the wild-type PMS2 gene would have tumor-suppressive effects while overexpressing S815L PMS2 mutant would negatively affect ovarian cancer cell proliferation. We tested three transfection conditions: pcDNA3 as a negative control variant, wild-type pcDNA3-PMS2, and pcDNA3-PMS2 mutated vectors. Using RT-PCR analysis, we optimized the transfection conditions for overexpression of both the wild-type PMS2 and mutant genes in OVCAR-3 cells. We acquired microscopic images to observe cell morphology and colonization. Also, we performed a Prestoblue assay to quantify the number of live cells in each condition. Results showed that the pcDNA3- PMS2 mutated vector has a higher cell proliferation than the wild-type vectors. As hypothesized, overexpressing the wild-type PMS2 gene had tumor-suppressive effects. This observation shows that the pcDNA3-PMS2 mutation has a tumor-progressive impact on the OVCAR-3 cells. Overall, we conclude that the PMS2 mutation has tumor-progressive effects in ovarian cancer cells while the unmutated version of the gene does not.

Immune Modulatory Properties of Collagen in Cancer.

During tumor growth the extracellular matrix (ECM) undergoes dramatic remodeling. The normal ECM is degraded and substituted with a tumor-specific ECM, which is often of higher collagen density and increased stiffness. The structure and collagen density of the tumor-specific ECM has been associated with poor prognosis in several types of cancer. However, the reason for this association is still largely unknown. Collagen can promote cancer cell growth and migration, but recent studies have shown that collagens can also affect the function and phenotype of various types of tumor-infiltrating immune cells such as tumor-associated macrophages (TAMs) and T cells. This suggests that tumor-associated collagen could have important immune modulatory functions within the tumor microenvironment, affecting cancer progression as well as the efficacy of cancer immunotherapy. The effects of tumor-associated collagen on immune cells could help explain why a high collagen density in tumors is often correlated with a poor prognosis. Knowledge about immune modulatory functions of collagen could potentially identify targets for improving current cancer therapies or for development of new treatments. In this review, the current knowledge about the ability of collagen to influence T cell activity will be summarized. This includes direct interactions with T cells as well as induction of immune suppressive activity in other immune cells such as macrophages. Additionally, the potential effects of collagen on the efficacy of cancer immunotherapy will be discussed.

S100a8/S100a9-Emmprin-Vegfa Axis Initiated By Tet2-Deficient Immune Cells Exacerbates Lung Cancer Progression through Promotion of Angiogenesis

Introductions:Loss-of-function TET2 mutations are frequent in clonal hematopoiesis in patients with solid cancers as well as that in healthy individuals. It remains to be elucidated whether and how TET2-mutated immune cells affect cancer progression in patients with TET2-mutated clonal hematopoiesis. Here, we assessed activity of Tet2-deficient immune cells using a mouse lung cancer model.Methods:Lewis Lung Carcinoma (LLC) cells were subcutaneously transplanted into blood-specific Mx-Cre or myeloid-specific LysM-Cre x Tet2 f/f mice (Tet2 -/- or Tet2 mye-) or control mice (CT). Single-cell RNA sequencing (scRNA-seq) was performed to determine the immune-cell profiles and mediators in tumors of Tet2 -/- mice (Tet2 -/- tumors). Whole transcriptome analysis (WTA) was also performed for granulocytic myeloid-derived cells (GMD), monocytic myeloid-derived cells (MMD), and tumor associated macrophages (TAM), as well as LLC cells sorted from Tet2 -/- tumors and CT tumors.Results:We found that tumor growth was enhanced in both Tet2 -/- and Tet2 mye- comparing to CT. Unsupervised clustering of scRNA-seq data identified 14 cell clusters: GMD into 3 (GMD1, GMD2, and GMD3), MMD into 5 (MMD1, MMD2, MMD3, MMD4, and MMD5), TAMs into 4 (TAM1, TAM2, TAM3, and TAM4), and DCs into 2 (DC1 and DC2). Notably, among all subclusters, the proportions of GMD1, GMD3, TAM3 and TAM4 were markedly expanded in Tet2 -/- tumors comparing to CT. Differentially expressed gene (DEG) analysis of scRNA-seq data found that S100a8 and S100a9 were highly expressed in Tet2-deficient GMD1 compared to CT. Furthermore, S100a8/S100a9 proteins were elevated in plasmas of Tet2 -/- comparing to those of CT. Pathway analysis using DEGs (p < 0.05) from WTA of GMD determined interleukin 1b (Il1b) signaling as upstream of S100a8/S100a9 activity. Gene set enrichment analysis (GSEA) also showed that 6 pathways related to Il1b were enriched in Tet2-deficient group compared to CT group. Gene ontology analysis (GO) for DEGs of GMD, MMD, and TAMs by WTA as well as 13 subclusters by scRNA-seq revealed that the “cellular response to IL-1” pathway was enriched in Tet2-deficient group compared to CT group. To define the downstream effectors in LLC cells, we performed WTA for LLC cells sorted from Tet2 -/- and CT tumors. We found that Vegfa, encoding a mediator for angiogenesis was highly upregulated in LLC cells sorted from Tet2 -/- tumors comparing to CT tumors. GSEA for WTA further identified that multiple Vegfa-related pathways as well as MAPK cascade were enriched in LLC cells from Tet2 -/- tumors comparing to those from CT tumors . Furthermore, S100a8/S100a9 induced Vegfa secretion from LLC cells in vitro. Remarkably, the area of blood vessels was increased in Tet2 -/- tumors comparing to CT tumors. Immunostaining exhibited that the number of Ly6g +GMD foci (>1000 px 2) expressing S100a8/S100a9 was increased in Tet2 -/- tumors comparing to CT tumors. Furthermore, LLC cells surrounding GMD foci highly expressed Vegfa in Tet2 -/- tumors. Finally, administration of an antibody against Emmprin, a receptor for S100a8/S100a9 inhibited the tumor growth in Tet2 -/-. Notably, the area of blood vessels in Tet2 -/- tumors with anti-Emmprin group was decreased at 2-fold compared to that seen in isotype group (p < 0.05). Consistently, S100A8/S100A9 induced VEGFA production in human lung cancer cells in vitro.Conclusions:Tet2-deificient immune cells promote lung cancer progression through S100a8/S100a9-Emmprin-Vegfa axis. Our study suggests a novel role of TET2-mutated clonal hematopoiesis in cancer progression and even provides a novel therapeutic target. DisclosuresNo relevant conflicts of interest to declare.

Prognostic evaluation and immune infiltration analysis of five bioinformatic selected genes in hepatocellular carcinoma.

Despite the development in hepatocellular carcinoma (HCC) treatment in recent years, the therapeutic outcome of HCC remains unfavourable. This study examines the prognosis of HCC from a genetic level using clinical databases and single‐cell data to identify genes with a high prognostic value. Three up‐regulated genes (UBE2S, PTTG1, and CDC20) and two down‐regulated genes (SOCS2 and DNASE1L3) in HCC tissues were identified. Various analyses confirmed its correlation with tumour stage (p < 0.01) and patient survival time (log‐rank p < 0.001). Immune analysis, single‐cell analysis, and gene set enrichment analysis (GSEA) were employed to provide insight on how they affect cancer progression, and we observed a close relation between these genes and tumour immune infiltration. Eventually, we constructed a risk score system that risk score = (0.0465) × UBE2S + (0.1851) × CDC20 + (−0.0461) × DNASE1L3 + (−0.2279) × SOCS2 (5‐year area under curve = 0.706). The risk score system may serve as an effective novel prognostic system for HCC patients. This study might provide novel ideas for prognostic or therapeutic biomarkers for HCC.