Favor Tumor Growth Research Articles

Bile's Hidden Weapon: Modulating the Microbiome and Tumor Microenvironment.

The human gut microbiome is a dynamic and intricate ecosystem, composed of trillions of microorganisms that play a pivotal role in maintaining overall health and well-being. However, the gut microbiome is constantly exposed to various environmental factors, including the bile produced by the liver, which can significantly impact its composition and function. Bile acids, secreted by the liver and stored in the gallbladder, modulate the gut microbiome, influencing its composition and function. This altered microbiome profile can, in turn, impact the tumor microenvironment (TME), promoting an immunosuppressive environment that favors tumor growth and metastasis. Furthermore, changes in the gut microbiome can also influence the production of bile acids and other metabolites that directly affect cancer cells and their behavior. Moreover, bile acids have been shown to shape the microbiome and increase antibiotic resistance, underscoring the need for targeted interventions. This review provides a comprehensive overview of the intricate relationships between bile, the gut microbiome, and the TME, highlighting the mechanisms by which this interplay drives cancer progression and resistance to therapy. Understanding these complex interactions is crucial for developing novel therapeutic strategies that target the gut-bile-TME axis and improve patient outcomes.

The role of NLRP3 and NLRP12 inflammasomes in glioblastoma.

Glioblastoma (GBM) is the deadliest malignant brain tumor, with a survival of less than 14 months after diagnosis. The highly invasive nature of GBM makes total surgical resection challenging, leading to tumor recurrence and declined survival. The heterocellular composition of the GBM reprograms its microenvironment, favoring tumor growth, proliferation, and migration. The innate immune cells in the GBM tumor microenvironment, including microglia, astrocytes, and macrophages, express pattern recognition receptors such as NLRs (Nucleotide-binding domain and leucine-rich repeat-containing) that sense pathogen- and damage-associated molecular patterns initiating inflammation. Upon activation, NLRP3 promotes inflammation by NLRP3 inflammasome formation. Auto-proteolytic cleavage and activation of Caspase-1 within the inflammasome leads to caspase-1-mediated cleavage, activation, and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. In contrast, NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-κB pathway. NLRP3 and NLRP12 have been implicated in the disease pathophysiology of several cancers with cell-context-dependent, pro- or anti-tumorigenic roles. In this review, we discuss the current literature on the mechanistic roles of NLRP3 and NLRP12 in GBM and the gaps in the scientific literature in the context of GBM pathophysiology with potential for targeted therapeutics.

Lactate-Induced HBEGF Shedding and EGFR Activation: Paving the Way to a New Anticancer Therapeutic Opportunity.

Cancer cells can release EGF-like peptides, acquiring the capacity of autocrine stimulation via EGFR-mediated signaling. One of these peptides (HBEGF) was found to be released from a membrane-bound precursor protein and is critically implicated in the proliferative potential of cancer cells. We observed that the increased lactate levels characterizing neoplastic tissues can induce the release of uPA, a protease promoting HBEGF shedding. This effect led to EGFR activation and increased ERK1/2 phosphorylation. Since EGFR-mediated signaling potentiates glycolytic metabolism, this phenomenon can induce a self-sustaining deleterious loop, favoring tumor growth. A well characterized HBEGF inhibitor is CRM197, a single-site variant of diphtheria toxin. We observed that, when administered individually, CRM197 did not trigger evident antineoplastic effects. However, its association with a uPA inhibitor caused dampening of EGFR-mediated signaling and apoptosis induction. Overall, our study highlights that the increased glycolytic metabolism and lactate production can foster the activated state of EGFR receptor and suggests that the inhibition of EGFR-mediated signaling can be attempted by means of CRM197 administered with an appropriate protease inhibitor. This attempt could help in overcoming the problem of the acquired resistance to the conventionally used EGFR inhibitors.

Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression.

Colorectal cancer (CRC) remains one of the most commonly diagnosed and deadliest types of cancer worldwide. CRC displays a desmoplastic reaction (DR) that has been inversely associated with poor prognosis; less DR is associated with a better prognosis. This reaction generates excessive connective tissue, in which cancer-associated fibroblasts (CAFs) are critical cells that form a part of the tumor microenvironment. CAFs are directly involved in tumorigenesis through different mechanisms. However, their role in immunosuppression in CRC is not well understood, and the precise role of signal transducers and activators of transcription (STATs) in mediating CAF activity in CRC remains unclear. Among the myriad chemical and biological factors that affect CAFs, different cytokines mediate their function by activating STAT signaling pathways. Thus, the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors. Here, we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

Deterministic reprogramming of neutrophils within tumors.

Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.

Dissection of paracrine/autocrine interplay in lung tumor microenvironment mimicking cancer cell-monocyte co-culture models reveals proteins that promote inflammation and metastasis

BackgroundTumor cell-monocyte interactions play crucial roles in shaping up the pro-tumorigenic phenotype and functional output of tumor-associated macrophages. Within the tumor microenvironment, such heterotypic cell–cell interactions are known to occur via secretory proteins. Secretory proteins establish a diabolic liaison between tumor cells and monocytes, leading to their recruitment, subsequent polarization and consequent tumor progression.MethodsWe co-cultured model lung adenocarcinoma cell line A549 with model monocytes, THP-1 to delineate the interactions between them. The levels of prototypical pro-inflammatory cytokines like TNF-\U0001d6fc, IL-6 and anti-inflammatory cytokines like IL-10 were measured by ELISA. Migration, invasion and attachment independence of lung cancer cells was assessed by wound healing, transwell invasion and colony formation assays respectively. The status of EMT was evaluated by immunofluorescence. Identification of secretory proteins differentially expressed in monocultures and co-culture was carried out using SILAC LC–MS/MS. Various insilico tools like Cytoscape, Reacfoam, CHAT and Kaplan–Meier plotter were utilized for association studies, pathway analysis, functional classification, cancer hallmark relevance and predicting the prognostic potential of the candidate secretory proteins respectively.ResultsCo-culture of A549 and THP-1 cells in 1:10 ratio showed early release of prototypical pro-inflammatory cytokines TNF-\U0001d6fc and IL-6, however anti-inflammatory cytokine, IL-10 was observed to be released at the highest time point. The conditioned medium obtained from this co-culture ratio promoted the migration, invasion and colony formation as well as the EMT of A549 cells. Co-culturing of A549 with THP-1 cells modulated the secretion of proteins involved in cell proliferation, migration, invasion, EMT, inflammation, angiogenesis and inhibition of apoptosis. Among these proteins Versican, Tetranectin, IGFBP2, TUBB4B, C2 and IFI30 were found to correlate with the inflammatory and pro-metastatic milieu observed in our experimental setup. Furthermore, dysregulated expression of these proteins was found to be associated with poor prognosis and negative disease outcomes in lung adenocarcinoma compared to other cancer types. Pharmacological interventions targeting these proteins may serve as useful therapeutic approaches in lung adenocarcinoma.ConclusionIn this study, we have demonstrated that the lung cancer cell-monocyte cross-talk modulates the secretion of IFI30, RNH1, CLEC3B, VCAN, IGFBP2, C2 and TUBB4B favoring tumor growth and metastasis.

Coculturing liver cancer cells and monocytes in spheroids conditions monocytes to adopt tumor-associated macrophage phenotypes that favor tumor growth via cholesterol metabolism.

Tumor-infiltrating immune cells and their crosstalk with cancer cells in the tumor microenvironment (TME) play a crucial role in shaping tumor progression and response to therapy. We utilized 3-dimensional liver cancer spheroids incorporating human primary monocytes to investigate the crosstalk between tumor-associated macrophages (TAMs) and Hepatocellular carcinoma (HCC) cells, HepG2 and PLC/PRF/5. Using multiplexed gene expression panels, the critical pathways involved in shaping primary human monocytes to adopt TAMs phenotypes were identified. The specific inhibitor for an identified pathway was used to explore its involvement in polarization of TAMs. In the cocultured spheroids comprising the human HCC cell lines, the infiltrating monocytes resembled protumor M2-like macrophage phenotypes. Gene expression panels of the infiltrating monocytes demonstrated that the upregulated genes were enriched in the cholesterol metabolism pathway. Cholesterol metabolism-related genes were upregulated together with the nuclear receptors, PPARG and LXR. When lysosomal acid lipase (LAL), the key enzyme necessary for the hydrolysis of lipoprotein, was inhibited, infiltrating monocytes in 3-dimensional spheroid coculture showed significantly decreased M2 marker and lipid uptake receptor expression as well as increased cellular lipid content, which indicated that cholesterol metabolism was important for conditioning the TAMs. Moreover, LAL inhibition reduced the spheroid growth and invasiveness of HCC cell lines. Small interfering RNA-mediated LAL silencing in monocytes yielded similar results upon spheroid coculture. These data indicated that liver cancer cells and infiltrating monocytes participate in crosstalk via cholesterol metabolism to condition monocytes toward TAMs, which favors tumor growth and survival, thereby promoting liver cancer progression.

The diversity and dynamics of tumor-associated macrophages in recurrent glioblastoma.

Despite tremendous efforts to exploit effective therapeutic strategies, most glioblastoma (GBM) inevitably relapse and become resistant to therapies, including radiotherapy and immunotherapy. The tumor microenvironment (TME) of recurrent GBM (rGBM) is highly immunosuppressive, dominated by tumor-associated macrophages (TAMs). TAMs consist of tissue-resident microglia and monocyte-derived macrophages (MDMs), which are essential for favoring tumor growth, invasion, angiogenesis, immune suppression, and therapeutic resistance; however, restricted by the absence of potent methods, the heterogeneity and plasticity of TAMs in rGBM remain incompletely investigated. Recent application of single-cell technologies, such as single-cell RNA-sequencing has enabled us to decipher the unforeseen diversity and dynamics of TAMs and to identify new subsets of TAMs which regulate anti-tumor immunity. Here, we first review hallmarks of the TME, progress and challenges of immunotherapy, and the biology of TAMs in the context of rGBM, including their origins, categories, and functions. Next, from a single-cell perspective, we highlight recent findings regarding the distinctions between tissue-resident microglia and MDMs, the identification and characterization of specific TAM subsets, and the dynamic alterations of TAMs during tumor progression and treatment. Last, we briefly discuss the potential of TAM-targeted strategies for combination immunotherapy in rGBM. We anticipate the comprehensive understanding of the diversity and dynamics of TAMs in rGBM will shed light on further improvement of immunotherapeutic efficacy in rGBM.

Mesothelin-targeted CAR-T therapy combined with irinotecan for the treatment of solid cancer.

Chimeric antigen receptor (CAR) T cell therapy has shown promising results in treating blood cancers, but it has limited efficacy against solid tumors that express mesothelin (MSLN). One of the reasons is the immunosuppressive tumor microenvironment, which consists of physical barriers, multiple mechanisms of immune evasion, and various biochemical factors that favor tumor growth and survival. These factors reduce the antitumor activity of MSLN-targeted CAR T cells in clinical trials. Therefore, new therapeutic strategies are needed to enhance the effectiveness of MSLN-targeted CAR T cell therapy. To investigate whether the antitumor efficacy of anti-MSLN CAR-T cells depends on the epitopes they recognize, we generated MSLN-targeted CAR T cells that bind to different regions of MSLN (Region I, II, III and Full length). We then evaluated the antitumor activity of MSLN-targeted CAR T cells alone or in combination with the chemotherapeutic drug irinotecan or an anti-PD-1 antibody in vitro and in vivo. We found that MSLN-targeted CAR T cells effectively killed MSLN-positive cancer cells (H9, H226 and Panc-1), but not MSLN-negative cells (A431) in vitro. In a mouse model of H9 tumor xenografts, all CAR T cells showed similar tumor suppression, but an MSLN-targeted scFv with Region I epitope, R47, performed slightly better. Combining irinotecan with CAR_R47 T cells enhanced tumor control synergistically in both H9 xenograft mice and patient-derived xenograft mice. Our results suggest that irinotecan can enhance the antitumor activity of MSLN-targeted CAR T cells, and offer a promising combination therapy strategy for MSLN-positive solid tumors.

Therapeutic Implications of PTEN in Non-Small Cell Lung Cancer.

Lung cancer remains one of the major human malignancies affecting both men and women worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent type. Multiple mechanisms have been identified that favor tumor growth as well as impede the efficacy of therapeutic regimens in lung cancer patients. Among tumor suppressor genes that play critical roles in regulating cancer growth, the phosphatase and tensin homolog (PTEN) constitutes one of the important family members implicated in controlling various functional activities of tumor cells, including cell proliferation, apoptosis, angiogenesis, and metastasis. Notably, clinical studies have also documented that lung tumors having an impaired, mutated, or loss of PTEN are associated with low survival or high tumor recurrence rates. To that end, PTEN has been explored as a promising target for anti-cancer agents. Importantly, the ability of PTEN to crosstalk with several signaling pathways provides new approaches to devise effective treatment options for lung cancer treatment. The current review highlights the significance of PTEN and its implications in therapeutic approaches against NSCLC.

The potential for citrate to reinforce epigenetic therapy by promoting apoptosis

Epigenetic drugs induce ATP depletion, promoting a glycolysis-to-oxidative phosphorylation (OXPHOS) shift which sometimes favors tumor growth by promoting necroptosis over apoptosis. To restore effective apoptosis in tumors, we propose that the administration of citrate could inhibit ATP production, activate caspase-8 (a key necroptosis inhibitor), and downregulate key anti-apoptotic proteins (Bcl-xL and MCL1).

High PD-L1 expression is associated with unfavorable clinical features in myelodysplastic neoplasms

Immune checkpoints are regulators of the immune system response that allow self-tolerance. Molecules such as Programmed Cell Death Protein 1 (PD-1) and its Ligand (PD-L1) participate in the immune checkpoint by signaling co-inhibition of lymphocyte responses. In cancers, PD-L1 expression is associated with the immune evasion mechanism, which favors tumor growth. The use of anti-PD-1/PD-L1 drugs is already well described in solid tumors, but still not fully understood in hematologic malignancies. Myelodysplastic neoplasms (MDSs) are heterogeneous bone marrow disorders with an increased risk of progression to Acute Myeloid Leukemia (AML). The MDS affects hematopoietic stem cells and its pathogenesis is linked to genetic and epigenetic defects, in addition to immune dysregulation. The influence of the PD-L1 on the MDS remains unknown. In this study, we evaluated the mRNA expression of the PD-L1 in 53 patients with MDS, classified according to the WHO 2016 Classification. Patients with dyserythropoiesis presented significantly higher PD-L1 expression than patients without dyserythropoiesis (p=0.050). Patients classified as having MDS with an excess of blasts 2 (MDS-EB2) presented a significant upregulation in the mRNA expression of the PD-L1 compared to the MDS with an excess of blasts 1 (MDS-EB1) (p=0.050). Furthermore, we detected three patients with very high levels of PD-L1 expression, being statistically classified as outliers. We suggested that the high expression of the PD-L1 is associated with a worse prognosis in the MDS and functional studies are necessary to evaluate the possible use of anti-PD-L1 therapies for high-risk MDS, such as the MDS-EBs.

Abstract 4063: Adoptive transfer of NF-kB p50 knockout immature myeloid cells shows a trend towards slower glioblastoma tumor growth in an orthotopic mouse model

Abstract Background: Glioblastoma (GBM) is a universally fatal brain tumor. Tumor-associated macrophages (TAMs) comprise up to 40% of GBM tumors and predominantly demonstrate an M2 phenotype, favoring tumor growth while suppressing host immune response. Previously, we showed that in p50-/- mice lacking the repressive NF-κB subunit, GBM TAMs are biased toward the pro-inflammatory M1 phenotype, limiting GBM tumor growth by increasing activated tumor T cells. The present study aims to determine whether adoptively transferred immature myeloid cells lacking p50 (p50-IMC) localize to mouse GBM tumors and slow tumor growth. Methods: Lineage-negative bone marrow (BM) cells were isolated from C57BL/6 (B6) p50-/- mice, expanded, and treated with Macrophage-Colony Stimulating Factor (M-CSF) for 24h to produce p50-IMC. BM-derived myeloid cells from both wild-type (WT) and p50-/- mice were subjected to analysis of M1 (TNFα, IL-12b) and M2 (Fizz1, Mannose Receptor) markers via quantitative PCR after exposure to M-CSF for 24h or after M2-polarization via five days in M-CSF and then two days in IL-4. B6-derived GL261-Luc GBM cells were inoculated intracranially into wild-type B6 mice, and four days post-implantation, mice were given 5-fluorouracil to deplete endogenous leukocytes. Mice then received either no additional treatment or three doses of ten million p50-IMCs 9-, 11-, and 14-days post-implantation, and tumor growth was monitored via bioluminescence, measured following luciferin injection using the Spectrum in vivo imaging system. The number of p50-IMCs localizing to the GBM-containing brain was determined by CFSE-dye-labeling of IMC followed by flow cytometry analysis 24h after injection. Results: Both TNFα and IL-12b were increased in p50-/- cells after 5 days M-CSF, and increased IL-12b expression was maintained even after M2-polarization with IL-4. Of the 10 million injected p50-IMCs, 0.07% of those cells were found in the brain. Despite such a small number of p50-IMCs localizing to the tissue of interest, inhibition of GBM growth was observed. Mice receiving the p50-IMC treatments (n = 4) demonstrated a 2.3- and 2.4-fold reduction in tumor growth at 15 (p = 0.13) and 18 (p = 0.14) days post-implantation, respectively, compared to control mice (n = 5). At 21 days post-implantation, tumor size was effectively equivalent between the two groups (p=0.76). p50-IMC treatment did not correlate with improved survival. Conclusion: Loss of p50 skews myeloid cells toward a proinflammatory phenotype, even under M2-polarizing conditions. Adoptive transfer of p50-IMC transiently impairs GBM growth in an orthotopic mouse model. Although statistical significance was not attained, this may be due to the small number of animals used in this experiment. Further investigation is needed to evaluate the full potential of p50-IMC as an immunotherapy option for GBM patients. Citation Format: Patrick J. Beck, Theresa Barberi, Alan D. Friedman. Adoptive transfer of NF-kB p50 knockout immature myeloid cells shows a trend towards slower glioblastoma tumor growth in an orthotopic mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4063.

The Mediterranean Lifestyle to Contrast Low-Grade Inflammation Behavior in Cancer.

A healthy diet and an active lifestyle are both effective ways to prevent, manage, and treat many diseases, including cancer. A healthy, well-balanced diet not only ensures that the body gets the right amount of nutrients to meet its needs, but it also lets the body get substances that protect against and/or prevent certain diseases. It is now clear that obesity is linked to long-term diseases such as heart disease, diabetes, and cancer. The main reasons for people being overweight or obese are having bad eating habits and not moving around enough. Maintaining weight in the normal range may be one of the best things to avoid cancer. It has been scientifically proven that those who perform regular physical activity are less likely to develop cancer than those who lead a sedentary lifestyle. Moving regularly not only helps to maintain a normal body weight, avoiding the effects that favor tumor growth in overweight subjects, but also makes the immune system more resistant by counteracting the growth of tumor cells. Physical activity also helps prevent cardiovascular and metabolic diseases. In this review, it is highlighted that the association between the Mediterranean diet and physical activity triggers biological mechanisms capable of counteracting the low-grade chronic inflammation found in patients with cancer. This assumes that healthy lifestyles associated with cancer therapies can improve the expectations and quality of life of cancer patients.

Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.

Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM. In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease. MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.

A primer on cancer-associated fibroblast mechanics and immunosuppressive ability.

Cancer-associated fibroblasts (CAFs) are a major point of interest in modern oncology. Their interest resides in their ability to favor tumor growth without carrying genetic mutations. From a translational standpoint, they are potential therapeutic targets, particularly for hard-to-treat solid cancers. CAFs can be defined as non-tumor cells within the tumor microenvironment that have the morphological traits of fibroblasts, are negative for lineage-specific markers (e.g., leukocyte, endothelium), and enhance tumor progression in a multi-pronged manner. Two often-mentioned aspects of CAF biology are their ability to alter the mechanics and architecture of the tumor microenvironment, and also to drive local immunosuppression. These two aspects are the specific focus of this work, which also contains a brief summary of novel therapeutic interventions under study to normalize or eliminate CAFs from the tumor microenvironment.

An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties.

Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFNγ to neoplastic lesions may be limited by the trapping of IFNγ-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFNγ with reduced affinity to its cognate receptor. The product (named L19-IFNγ KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFNγ KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1.

Immunohistochemical Expression of Cath-D as Prognostic Biological Marker and its Correlation with Clinical and Histopathological Parameters in Human Breast Cancer

Cathepsin D (Cath-D) is a soluble lysosomal aspartyl glycoprotease that can degrade the protein components of the matrix and free growth factors therein embedded, thus favoring tumor growth, invasion and angiogenesis. The aim of the present work was to investigate the expression of Cathepsin D as novel prognostic biomarker in human invasive ductal carcinoma (IDC) versus benign tumors and normal breast tissues as well as their correlation with different pathological and histological parameters. Immunohistochemical technique was used to examine the expression of Cath-D in normal, benign as well as in IDC. Present results showed higher expression of Cath-D in IDC comparing to normal and benign breast tissues.

Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer

Breast cancer (BC) is the most common malignancy in women worldwide. While the main systemic treatment option is anthracycline-containing chemotherapy, chemoresistance continues to be an obstacle to patient survival. Carnitine palmitoyltransferase 1C (CPT1C) has been described as a poor-prognosis marker for several tumour types, as it favours tumour growth and hinders cells from entering senescence. At the molecular level, CPT1C has been associated with lipid metabolism regulation and important lipidome changes. Since plasma membrane (PM) rigidity has been associated with reduced drug uptake, we explored whether CPT1C expression could be involved in PM remodelling and drug chemoresistance. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) lipid analysis of PM-enriched fractions of MDA-MB-231 BC cells showed that CPT1C silencing increased PM phospholipid saturation, suggesting a rise in PM rigidity. Moreover, CPT1C silencing increased cell survival against doxorubicin (DOX) treatment in different BC cells due to reduced drug uptake. These findings, further complemented by ROC plotter analysis correlating lower CPT1C expression with a lower pathological complete response to anthracyclines in patients with more aggressive types of BC, suggest CPT1C as a novel predictive biomarker for BC chemotherapy.

Immunohistochemical Expression of Fn14 and Cath-D as Prognostic Biological Markers and Compare with Histological Reaction in Invasive Human Breast Cancer

Fibroblast growth factor-inducible-14 (Fn14) is a 14-kDa type I transmembrane receptor located on chromosome 16p13. Fn14 is a member of the tumor necrosis factor receptor super family that normally expressed in healthy tissues, but its expression is increased in injured tissue where it thought to play role in tissue remodeling. Cathepsin D (Cath-D) is a soluble lysosomal aspartyl glycoprotease that can degrade the protein components of the matrix and free growth factors therein embedded, thus favoring tumor growth, invasion and angiogenesis. The aim of the present work was to investigate the expression of Fn14 and Cathepsin D as novel prognostic biomarkers in human invasive ductal carcinoma (IDC) versus benign tumors and normal breast tissues as well as their correlation with different pathological and histological parameters. Immunohistochemical technique was used to examine the expression of Fn14 and Cath-D in normal, benign as well as in IDC. Present results showed higher expression of Fn14 and Cath-D in IDC comparing to normal and benign breast tissues.