Breast cancer is a complex disease with significant phenotypic heterogeneity of cells, even within a single breast tumor. Emerging evidence underscores the significance of intratumoral competition, which can serve as a key contributor to cancer drug resistance, imparting substantial clinical implications. Understanding the competitive dynamics is paramount as it can significantly influence disease progression and treatment outcomes. In the present work, a mathematical model was developed using a system of differential equations to describe the dynamic interactions between two cancer subtypes (each further classified into cancer stem cells and tumor cells) and innate immune cells. The purpose of the model is to comprehensively understand the competitive interactions between the heterogeneous subpopulations. The equilibrium points and stability analysis for each equilibrium point were established. Model simulations showed that the competition between two cancer subtypes directly affects the number of both species. When competition between two cancer subtypes is strong, increasing the immune response rate specific to the more competitive species effectively reduces the tumor size. However, if the competition is relatively weak, an optimal immune response rate is required to minimize the total number of tumor cells. Rates below the optimal level fail to reduce the population of the stronger species, whereas rates above the optimal level can lead to the recurrence of the weaker species. Overall, this model provides insights into breast cancer dynamics and guides the development of effective treatment strategies.

BACKGROUND: Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle.
METHODS: We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Nav) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Nav activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Nav in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo.
RESULTS: We demonstrated that Nav is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Nav made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Nav substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Nav positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Nav.
CONCLUSIONS: This insight positions Nav as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment.

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Pirarubicin attracted considerable attention in clinical studies because of its high therapeutic efficacy and reduced toxicity in comparison with other anthracyclines. Nevertheless, ~ 30% patients undergoing PIRA treatment still experience relapse and metastasis. Clinical advancements unveiled that cancer stem cells (CSCs) residing in the tumor constitutes a major factor for such limitations and subsequently are the reason for treatment failure. Consequently, eradicating CSCs alongside bulk tumor is a crucial undertaking to attain utmost therapeutic efficacy of the treatment. Nevertheless, majority of the CSCs inhibitors currently under examination lack specificity, show unsynchronized bioavailability with other primary treatments and exhibit notable toxicity in their therapeutic applications, which is primarily attributable to their inadequate tumor-targeting capabilities. Therefore, we have developed a biodegradable polylactic acid based blend block copolymeric NPs for concomitant delivery of CSCs inhibitor Salinomycin (SAL) & chemotherapeutic drug Pirarubicin (PIRA) with an aim to improve the efficacy of treatment and prevent cancer relapse. Prepared NPs showed < 100 nm size and excellent loading with sustained release for both the drugs. Also, PIRA:SAL co-loaded NPs exhibits synergistically enhanced cytotoxicity against cancer cell as well as CSCs. Most importantly, NPs mediated co-delivery of the drugs showed complete tumor eradication, without any reoccurrence throughout the surveillance period. Additionally, NPs treatment didn\'t show any histopathological alteration in vital organs confirming their non-toxic nature. Altogether, present study concludes that the developed PIRA:SAL NPs have excellent efficacy for tumor regression as well as prevention of cancer relapse, hence can be used as a potential combination therapy for cancer treatment.

Despite recent advances in cancer diagnostics and treatment, the mortality associated with lung cancer is still the highest in the world. Late-stage diagnosis, often accompanied by metastasis, is a major contributor to the high mortality rates, emphasizing the urgent need for reliable and readily accessible diagnostic tools that can detect biomarkers unique to lung cancer. Circulating factors, such as circulating tumor DNA and extracellular vesicles, from liquid biopsy have been recognized as diagnostic or prognostic markers in lung cancer. Numerous clinical studies are currently underway to investigate the potential of circulating tumor DNA, circulating tumor RNA, exosomes, and exosomal microRNA within the context of lung cancer. Those clinical studies aim to address the poor diagnostics and limited treatment options for lung cancer, with the ultimate goal of developing clinical markers and personalized therapies. In this review, we discuss the roles of each circulating factor, its current research status, and ongoing clinical studies of circulating factors in non-small cell lung cancer. Additionally, we discuss the circulating factors specifically found in lung cancer stem cells and examine approved diagnostic assays designed to detect circulating biomarkers in lung cancer patients.

UNASSIGNED: Breast cancer stem cells (BCSCs) have been suggested to be responsible for the development of Breast cancer (BC). The aim of this study was to evaluate BCSCs and the target organs microenvironment immunophenotyping markers in common BC metastases, and therapeutic targets regarding to the mentioned criteria.
UNASSIGNED: This narrative review involved searching international databases; PubMed, Google Scholar using predetermined keywords including breast cancer, breast cancer stem cells, breast cancer metastases, immunophenotyping, immunohistochemistry and metastases. The search results were assessed based on the title, abstract, and full text of the articles, and relevant findings were included in the review.
UNASSIGNED: BCSCs express high amounts of aldehyde dehydrogenase 1 (ALDH1), Ganglioside 2 (GD2), CD44 and CD133 but are negative for CD24 marker. CXCR4 and OPN have high expression in the cells and may contribute in BC metastasis to the bone. Nestin, CK5, prominin-1 (CD133) markers in BCSCs have been reported to correlate with brain metastasis. High expression of CD44 in BCSCs and CXCL12 expression in the liver microenvironment may contribute to BC metastasis to the liver. Aberrantly expressed vascular cell adhesion molecule-1 (VCAM-1) that binds to collagen and elastin fibers on pulmonary parenchyma, and CXCR4 of BCSCs and CXCL12 in lung microenvironment may promote the cells homing and metastasis to lung.
UNASSIGNED: As in various types of BC metastases different markers that expressed by the cells and target organ microenvironment are responsible, BCSCs immunophenotyping can be used as target markers to predict the disease prognosis and treatment.

BACKGROUND: Increased cancer stem cell (CSC) content and SOX2 overexpression are common features in the development of resistance to therapy in hormone-dependent breast cancer, which remains an important clinical challenge. SOX2 has potential as biomarker of resistance to treatment and as therapeutic target, but targeting transcription factors is also challenging. Here, we examine the potential inhibitory effect of different polyoxometalate (POM) derivatives on SOX2 transcription factor in tamoxifen-resistant breast cancer cells.
METHODS: Various POM derivatives were synthesised and characterised by infrared spectra, powder X-ray diffraction pattern and nuclear magnetic resonance spectroscopy. Estrogen receptor (ER) positive breast cancer cells, and their counterparts, which have developed resistance to the hormone therapy tamoxifen, were treated with POMs and their consequences assessed by gel retardation and chromatin immunoprecipitation to determine SOX2 binding to DNA. Effects on proliferation, migration, invasion and tumorigenicity were monitored and quantified using microscopy, clone formation, transwell, wound healing assays, flow cytometry and in vivo chick chorioallantoic membrane (CAM) models. Generation of lentiviral stable gene silencing and gene knock-out using CRISPR-Cas9 genome editing were applied to validate the inhibitory effects of the selected POM. Cancer stem cell subpopulations were quantified by mammosphere formation assays, ALDEFLUOR activity and CD44/CD24 stainings. Flow cytometry and western blotting were used to measure reactive oxygen species (ROS) and apoptosis.
RESULTS: POMs blocked in vitro binding activity of endogenous SOX2. [P2W18O62]6- (PW) Wells-Dawson-type anion was the most effective at inhibiting proliferation in various cell line models of tamoxifen resistance. 10 µM PW also reduced cancer cell migration and invasion, as well as SNAI2 expression levels. Treatment of tamoxifen-resistant cells with PW impaired tumour formation by reducing CSC content, in a SOX2-dependent manner, which led to stem cell depletion in vivo. Mechanistically, PW induced formation of reactive oxygen species (ROS) and inhibited Bcl-2, leading to the death of tamoxifen-resistant cells. PW-treated tamoxifen-resistant cells showed restored sensitivity to tamoxifen.
CONCLUSIONS: Together, these observations highlight the potential use of PW as a SOX2 inhibitor and the therapeutic relevance of targeting SOX2 to treat tamoxifen-resistant breast cancer.

Human ALDH comprise 19 subfamilies in which ALDH1A1, ALDH1A3, ALDH3A1, ALDH5A1, ALDH7A1, and ALDH18A1 are implicated in CSC. Studies have shown that ALDH can also be involved in drug resistance and standard chemotherapy regimens are ineffective in treating patients at the stage of disease recurrence. Existing chemotherapeutic drugs eliminate the bulk of tumors but are usually not effective against CSC which express ALDH+ population. Henceforth, targeting ALDH is convincing to treat the patient\'s post-relapse. Combination therapies that interlink signaling mechanisms seem promising to increase the overall disease-free survival rate. Therefore, targeting ALDH through ALDH inhibitors along with immunotherapies may create a novel platform for translational research. This review aims to fill in the gap between ALDH1 family members in relation to its cell signaling mechanisms, highlighting their potential as molecular targets to sensitize recurrent tumors and bring forward the future development concerning the current progress and draw backs. This review summarizes the role of cancer stem cells and their upregulation by maintaining the tumor microenvironment in which ALDH is specifically highlighted. It discusses the regulation of ALDH family proteins and the crosstalk between ALDH and CSC in relation to cancer metabolism. Furthermore, it establishes the correlation between ALDH involved signaling mechanisms and their specific targeted inhibitors, as well as their functional modularity, bioavailability, and mechanistic role in various cancers.

Most patients diagnosed with pancreatic cancer are initially at an advanced stage, and radiotherapy resistance impact the effectiveness of treatment. This study aims to investigate the effects of endocrine disruptor Di-(2-ethylhexyl) phthalate (DEHP) on various biological behaviors and the radiotherapy sensitivity of pancreatic cancer cells, as well as its potential mechanisms. Our findings indicate that exposure to DEHP promotes the proliferation of various cancer cells, including those from the lung, breast, pancreas, and liver, in a time- and concentration-dependent manner. Furthermore, DEHP exposure could influence several biological behaviors of pancreatic cancer cells in vivo and vitro. These effects include reducing cell apoptosis, causing G0/G1 phase arrest, increasing migration capacity, enhancing tumorigenicity, elevating the proportion of cancer stem cells (CSCs), and upregulating expression levels of CSCs markers such as CD133 and BMI1. DEHP exposure can also increase radiation resistance, which can be reversed by downregulating BMI1 expression. In summary our research suggests that DEHP exposure can lead to pancreatic cancer progression and radiotherapy resistance, and the mechanism may be related to the upregulation of BMI1 expression, which leads to the increase of CSCs properties.

Cancer stem cells (CSCs), the master regulators of tumor heterogeneity and progression, exert profound influence on cancer metastasis, via various secretory vesicles. Emerging from CSCs, the exosomes serve as pivotal mediators of intercellular communication within the tumor microenvironment, modulating invasion, angiogenesis, and immune responses. Moreover, CSC-derived exosomes play a central role in sculpting a dynamic landscape, contributing to the malignant phenotype. Amidst several exosomal cargoes, misfolded proteins have recently gained attention for their dual functions in maintaining protein homeostasis and promoting tumor progression. Disrupting these communication pathways could potentially prevent the maintenance and expansion of CSCs, overcome treatment resistance, and inhibit the supportive environment created by the tumor microenvironment, thereby improving the effectiveness of cancer therapies and reducing the risk of tumor recurrence and metastasis. Additionally, exosomes have also shown potential therapeutic applications, such as in drug delivery or as biomarkers for cancer diagnosis and prognosis. Therefore, comprehending the biology of exosomes derived from CSCs is a multifaceted area of research with implications in both basic sciences and clinical applications. This review explores the intricate interplay between exosomal misfolded proteins released by CSCs, the potent contributor in tumor heterogeneity, and their impact on cellular processes, shedding light on their role in cancer progression.