Formation Of Secondary Tumors Research Articles

SERM Therapy for patients of breast cancer and otherwise.

Madam, In Pakistan, the most frequently diagnosed cancer among females is breast cancer, where every year at least 90,000 women suffer from the disease [1]. This incidence is 2.5 times higher than that of Pakistan’s neighbouring countries and the highest in Asia[1]. The current treatments for breast cancer in the country are all invasive forms of therapy and include radiation therapy, chemotherapy, lymph node removal, and mastectomy. This letter aims to draw attention to a newer form of treatment for breast cancer known as selective estrogen receptor modulators (SERMs). Selective estrogen receptor modulators (SERMs) are synthetic molecules that provide a non-invasive therapy for breast cancer patients. Recent studies have proposed that the specificity of SERM’s mechanism of action and antiviral properties yield fruitful outcomes in treating covid-positive breast cancer patients [2], giving SERMs a significant advantage over former treatments such as radiation therapy or chemotherapy which reduce the body’s ability to fight infections. SERMs block the effects of estrogen on breast tissue, preventing cancer cells from dividing. They also act as an adjuvant in breast cancer therapy [3], suppressing secondary tumor formation. A recent study published in the Journal of Clinical Oncology showed significant benefits from two years of tamoxifen therapy in estrogen receptor- positive premenopausal patients of breast cancer [4]. On various other tissues, they act as estrogen, allowing for their use alongside other treatments for postmenopausal women to prevent bone loss and osteoporosis [3]. Despite SERM ‘s wide range of benefits in patients with breast cancer, it is not a fully recognized form of treatment for this population in Pakistan. Such hormonal therapy is only offered by a handful of high-end private-sector hospitals. This is attributed to a lack of research in this area due to various socio-economic factors. A limited choice of treatment for women with breast cancer in Pakistan results from fear of stigmatization and feminine sensitivity [5]. Attention should be brought to alternative therapies for breast cancer treatment to improve prognosis and help patients make the best possible shared decision-making choices.

Prospects of epigenetic therapy of head and neck squamous cell carcinoma

Introduction. Head and neck squamous cell carcinoma is the 6th most common malignant tumor. It is characterized by immune response evasion and drug resistance. To stimulate antitumor immune response, antibodies against such cell cycle checkpoints as programmed cell death 1 (pD-1) and programmed death-ligand 1 (pD-L1) are used. However, effectiveness of monotherapy with these checkpoint inhibitors turned out to be low, and combinations with other antitumor drugs have high risk of adverse events.Aim. To determine the most practical ways to influence epigenetic factors in treatment of head and neck squamous cell carcinoma.Materials and methods. Scientific literature published between 2011 and 2022 and indexed in the eLIBRARY, Scopus, woS, NCBI databases (398 articles, of which 76 were used) was analyzed.Results. prospects of development of epigenetic stimulation of expression of retroelements located in tumor genomes through inhibition of DNA methyltransferases, deacetylases and histone methyltransferases were considered. when retroelements are activated, their transcripts form double-stranded RNA stimulating T killers and interferon response (virus mimicry). for DNA methyltransferase inhibitors, restoration of tumor suppressor genes which are hypermethylated in squamous cell carcinoma is also observed. However, retroelement activation is a driver mechanism of carcinogenesis, and their nonspecific expression can lead to tumor progression and formation of secondary tumors. Therefore, in the virus mimicry method it is practical to use as targets microRNA complementary to retroelements which recruit epigenetic factors to their loci (RNA-directed DNA methylation), as well as antisense oligonucleotides against oncogenic microRNA associated with retroelements. These approaches allow to inhibit retroelements participating in carcinogenesis. Nonspecific method of retrotransposon activity suppression is being developed in antitumor therapy, but data show successful application of only reverse transcriptase inhibitors preventing insertions and progression of genomic instability. we have performed analysis of scientific literature on transposable elements-derived microRNA associated with head and neck squamous cell carcinoma. As a result, 31 microRNAs were identified, derived from: LINE: miR-1249, -151a, -211, -2355, -28, -31, -3144, -374a, -374b, -421, -450b, -511, -576, -577, -582, -708, -769, -887, -95; HERv: miR-1269a, -1911, -3200, -495; non-autonomous SINE: miR-335, -342, -378a, -3934, -487b; DNA transposons: miR-224, -584, -652. These microRNAs can serve as the basis for epigenetic therapy of head and neck squamous cell carcinoma.

Lighting up metastasis process before formation of secondary tumor by phosphorescence imaging.

Metastasis is the leading cause of cancer-related deaths; until now, the detection of tumor metastasis is mainly located at the period that secondary tumors have been formed, which usually results in poor prognosis. Thus, fast and precise positioning of organs, where tumor metastases are likely to occur at its earliest stages, is essential for improving patient outcomes. Here, we demonstrated a phosphorescence imaging method by organic nanoparticles to detect early tumor metastasis progress with microenvironmental changes, putting the detection period ahead to the formation of secondary tumors. In the orthotopic and simulated hematological tumor metastasis models, the microenvironmental changes could be recognized by phosphorescence imaging at day 3, after tumor implantation in liver or intravenous injection of cancer cells. It was far ahead those of other reported imaging methods with at least 7 days later, providing a sensitive and convenient method to monitor tumor metastases at the early stage.

Self-assembled multifunctional nanotheranostics against circulating tumor clusters in metastatic breast cancer.

Circulating tumor clusters (CTC) disseminating from the primary tumor are responsible for secondary tumor formation where the conventional treatments such as chemotherapy and radiotherapy does not prevent the metastasis at locally advanced stage of breast cancer. In this study, a smart nanotheranostic system has been developed to track and eliminate the CTCs before it can colonize at a new site, which would reduce metastatic progression and increase the five-year survival rate of the breast cancer patients. Targeted multiresponsive (magnetic hyperthermia and pH) nanomicelles incorporated with NIR fluorescent superparamagnetic iron oxide nanoparticles were developed based on self-assembly for dual modal imaging and dual toxicity for spontaneous killing of CTCs in blood stream. A heterogenous tumor clusters model was developed to mimic the CTCs isolated from breast cancer patients. The nanotheranostic system was further evaluated for the targeting property, drug release kinetics, hyperthermia and cytotoxicity against developed CTC model invitro. Invivo model in BALB/c mice equivalent to stage III and IV human metastatic breast cancer was developed to evaluate the biodistribution and therapeutic efficacy of micellar nanotheranostic system. Reduced CTCs in blood stream and low distant organ metastasis after treatment with the nanotheranostic system demonstrates its potential to capture and kill the CTCs that minimize the secondary tumor formation at distant sites.

Small molecule ‘4ab’ induced autophagy and endoplasmic reticulum stress-mediated death of aggressive cancer cells grown under adherent and floating conditions

Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress inagressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally,was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent. Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of thereby causing apoptosisin aggressive cancer cells.

Brain metastasis in breast cancer: focus on genes and signaling pathways involved, blood-brain barrier and treatment strategies.

Breast cancer(BC) is one of the most prevalent types of cancer in women. Despite advancement in early detection and efficient treatment, recurrence and metastasis continue to pose a significant risk to the life of BC patients. Brain metastasis(BM) reported in 17-20 percent of BC patients is considered as a major cause of mortality and morbidity in these patients. BM includes various steps from primary breast tumor to secondary tumor formation. Various steps involved are primary tumor formation, angiogenesis, invasion, extravasation, and brain colonization. Genes involved in different pathways have been reported to be associated with BC cells metastasizing to the brain. ADAM8 gene, EN1 transcription factor, WNT, and VEGF signaling pathway have been associated with primary breast tumor; MMP1, COX2, XCR4, PI3k/Akt, ERK and MAPK pathways in angiogenesis; Noth, CD44, Zo-1, CEMIP, S0X2 and OLIG2 are involved in invasion, extravasation and colonization, respectively. In addition, the blood-brain barrier is also a key factor in BM. Dysregulation of cell junctions, tumor microenvironment and loss of function of microglia leads to BBB disruption ultimately resulting in BM. Various therapeutic strategies are currently used to control the BM in BC. Oncolytic virus therapy, immune checkpoint inhibitors, mTOR-PI3k inhibitors and immunotherapy have been developed to target various genes involved in BM in BC. In addition, RNA interference (RNAi) and CRISPR/Cas9 are novel interventions in the field of BCBM where research to validate these and clinical trials are being carried out. Gaining a better knowledge of metastasis biology is critical for establishing better treatment methods and attaining long-term therapeutic efficacies against BC. The current review has been compiled with an aim to evaluate the role of various genes and signaling pathways involved in multiple steps of BM in BC. The therapeutic strategies being used currently and the novel ones being explored to control BM in BC have also been discussed at length.

Prostate cancer bone metastases biology and clinical management (Review).

Prostate cancer (PCa) is one of the most prominent causes of cancer-related mortality in the male population. A highly impactful prognostic factor for patients diagnosed with PCa is the presence or absence of bone metastases. The formation of secondary tumours at the bone is the most commonly observed site for the establishment of PCa metastases and is associated with reduced survival of patients in addition to a cohort of life-debilitating symptoms, including mobility issues and chronic pain. Despite the prevalence of this disease presentation and the high medical relevance of bone metastases, the mechanisms underlying the formation of metastases to the bone and the understanding of what drives the osteotropism exhibited by prostate tumours remain to be fully elucidated. This lack of in-depth understanding manifests in limited effective treatment options for patients with advanced metastatic PCa and culminates in the low rate of survival observed for this sub-set of patients. The present review aims to summarise the most recent promising advances in the understanding of how and why prostate tumours metastasise to the bone, with the ultimate aim of highlighting novel treatment and prognostic targets, which may provide the opportunity to improve the diagnosis and treatment of patients with PCa with bone metastases.

Multifunctional biomimetic nanoplatform based on photodynamic therapy and DNA repair intervention for the synergistic treatment of breast cancer.

Photodynamic therapy (PDT) is a minimally invasive and locally effective treatment method, which has been used in the clinical treatment of a variety of superficial tumors. In recent years, PDT has received extensive attention due to its induction of immunogenic cell death (ICD). However, the repair mechanism of tumor cells and low immune response limit the further development of PDT. To this end, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) is developed to co-deliver the photosensitizer Chlorin e6 (Ce6) and Olaparib (Ola) with the function of preventing DNA repair. The nanoplatform shows efficient tumor targeting and cellular internalization properties due to cell membrane camouflage, and Ce6 and Ola produce a significant synergistic anti-tumor effect under laser irradiation. Meanwhile, the nanoplatform can also activate the cyclic guanosine monophosphate-adenosine monophosphate synthase-interferon gene stimulator signaling (cGAS-STING) pathway to produce cytokines. The damage-associated molecular patterns induced by ICD can work with these cytokines to recruit and stimulate the maturation of dendritic cells and induce the systemic anti-tumor immune response. Overall, this multifunctional biomimetic nanoplatform integrating PDT, chemotherapy, and immunotherapy is highlighted here to boost anti-tumor therapy. STATEMENT OF SIGNIFICANCE: Self-repair of DNA damage is the most important reason for the failure of primary tumor eradication and the formation of secondary and metastatic tumors. To address this issue, a multifunctional biomimetic nanoplatform 4T1Mem@PGA-Ce6/Ola (MPCO) was developed to integrate a photosensitizer Chlorine a6 and a poly (ADP-ribose) polymerase inhibitor Olaparib. With tumor targeting ability and controlled release of drugs, the MPCO was expected to enhance tumor immunogenicity and facilitate antitumor immunity through the induction of immunogenic cell death as well as the activation of the cGAS-STING pathway. This study develops a promising combination strategy against tumors and has substantial implications for the prognosis of patients with breast cancer.

Identification of lysyl oxidase as an adipocyte-secreted mediator that promotes a partial mesenchymal-to-epithelial transition in MDA-MB-231 cells.

Breast cancer (BC) is the most common cancer in women worldwide, where adiposity has been linked to BC morbidity. In general, obese premenopausal women diagnosed with triple-negative BC (TNBC) tend to have larger tumours with more metastases, particularly to the bone marrow, and worse prognosis. Previous work using a 3-dimensional (3D) co-culture system consisting of TNBC cells, adipocytes and the laminin-rich extracellular matrix (ECM) trademarked as Matrigel, demonstrated that adipocytes and adipocyte-derived conditioned media (CM) caused a partial mesenchymal-to-epithelial transition (MET). Given that MET has been associated with secondary tumour formation, this study sought to identify molecular mediators responsible for this phenotypic change. Adipocytes were cultured with and without Matrigel, where semi-quantitative proteomics was used to identify proteins whose presence in the CM was induced or enhanced by Matrigel, which were referred to as adipocyte-secreted ECM-induced proteins (AEPs). The AEPs identified were assessed for association with prognosis in published proteomic datasets and prior literature. Of these, 4 were evaluated by the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), followed by a functional and MET marker analysis of 1 AEP on MDA-MB-231 cells grown on Matrigel or as monolayers. The 4 AEPs showed a positive correlation between protein expression and poor prognosis. RT-qPCR analysis reported no significant change in AEPs mRNA expression. However, lysyl oxidase (LOX) was increased in CM of ECM-exposed adipocytes. Recombinant LOX (rLOX) caused the mesenchymal MDA-MB-231 TNBC cells to form less branched 3D structures and reduced the expression of vimentin. The data suggest that adipocyte-secreted LOX changes the mesenchymal phenotype of BC cells in a manner that could promote secondary tumour formation, particularly at sites high in adipocytes such as the bone marrow. Future efforts should focus on determining whether targeting LOX could reduce BC metastasis in obese individuals.

Subrenal Capsule Assay - SRCA: The Promising Re-Emergence of a Long-Forgotten Method in Preclinical Nuclear Medical Cancer Diagnostics.

Since metastases are responsible for the majority of cancer-related death, in-depth understanding of metastatisation may provide an opportunity for the introduction of new therapeutic as well as diagnostic approaches in cancer management. Previously, preclinical research into the development and progression of malignancies has been hampered by the relative paucity of in vivo tumor models. Subrenal capsule assay (SRCA)-induced tumor-bearing experimental animal models, however, serve as potential preclinical model systems for the assessment of primary tumors and the route of metastatic spread. Several studies implementing either Hepatocarcinoma (He/De), Mesoblastic Nephroma (Ne/De), chemically induced Myeloid Leukemia (My1/De), or spontaneous Myeloid Myelomonocytic Leukemia (My2/De) cells under the left renal capsule of rats applying SRCA method were underway to study secondary tumor formation. Based on the results of this research, subrenally transplanted neoplastic cells led to the appearance of metastasis in the parathymic lymph nodes. Therefore, renal capsule/parathymic lymph node complex seems to be valuable in the in vivo evaluation of the process of metastatisation and the occurrence of secondary neoplasms. The re-emergence of this highly promising SRCA-based renal capsule/parathymic lymph node complex in preclinical nuclear medicine and experimental oncology may open a novel field towards drug trials and radiopharmaceutical development. In the present review, we provide a detailed overview of the history of SRCA as well as the series of research on the establishment of renal capsule/parathymic lymph node complex.

Cancer Stem Cells-The Insight into Non-Coding RNAs.

Since their initial identification three decades ago, there has been extensive research regarding cancer stem cells (CSCs). It is important to consider the biology of cancer stem cells with a particular focus on their phenotypic and metabolic plasticity, the most important signaling pathways, and non-coding RNAs (ncRNAs) regulating these cellular entities. Furthermore, the current status of therapeutic approaches against CSCs is an important consideration regarding employing the technology to improve human health. Cancer stem cells have claimed to be one of the most important group of cells for the development of several common cancers as they dictate features, such as resistance to radio- and chemotherapy, metastasis, and secondary tumor formation. Therapies which could target these cells may develop into an effective strategy for tumor eradication and a hope for patients for whom this disease remains uncurable.

Cancer and Associated Recent Findings on Metastasis

Background: Cancer is one of the disease with up rised constant mutations and difficult to cure due to metastatic tumors and cell- cell communications between the tumors and the cell through stromal microenvironment and cell signaling.
 Discussion: Integrin α11β1 acts as a stromal receptor and remodifies collagen through communication between the stroma and collagen related genes contributing majorly to metastasis in NSCLC. Extracellular matrix protein-1, Osteopontin and Osteonectin are the secreted proteins which are differentially expressed based on the metastatic phenotype. Thrombospondin-1 is responsible for migratory property of the wild cells by promoting intravasation and hyperplasia in many cancers like prostate cancer. Hemopexin and Ferritin light chain (FTL) are the proteins majorly expressed in cancer cell cytoplasm and stromal fibroblasts and contribute to metastasis through secretions mediated by extracellular vesicles.
 Conclusion: Other proteins like TWIST, BRCA-1, BRCA-2, cell adhesion proteins, MMPs, Tetraspanin can contribute to metastasis in cancer through promoting either cell migration, Extravasation, Hyperplasia or Angiogenesis facilitating the secondary tumor formation in distant organs.

Selective Inhibition of Bruton's Tyrosine Kinase by a Designed Covalent Ligand Leads to Potent Therapeutic Efficacy in Blood Cancers Relative to Clinically Used Inhibitors.

Bruton's tyrosine kinase (BTK) is a member of the TEC-family kinases and crucial for the proliferation and differentiation of B-cells. We evaluated the therapeutic potential of a covalent inhibitor (JS25) with nanomolar potency against BTK and with a more desirable selectivity and inhibitory profile compared to the FDA-approved BTK inhibitors ibrutinib and acalabrutinib. Structural prediction of the BTK/JS25 complex revealed sequestration of Tyr551 that leads to BTK's inactivation. JS25 also inhibited the proliferation of myeloid and lymphoid B-cell cancer cell lines. Its therapeutic potential was further tested against ibrutinib in preclinical models of B-cell cancers. JS25 treatment induced a more pronounced cell death in a murine xenograft model of Burkitt's lymphoma, causing a 30-40% reduction of the subcutaneous tumor and an overall reduction in the percentage of metastasis and secondary tumor formation. In a patient model of diffuse large B-cell lymphoma, the drug response of JS25 was higher than that of ibrutinib, leading to a 64% "on-target" efficacy. Finally, in zebrafish patient-derived xenografts of chronic lymphocytic leukemia, JS25 was faster and more effective in decreasing tumor burden, producing superior therapeutic effects compared to ibrutinib. We expect JS25 to become therapeutically relevant as a BTK inhibitor and to find applications in the treatment of hematological cancers and other pathologies with unmet clinical treatment.

Single-cell RNA-sequencing identifies anti-cancer immune phenotypes in the early lung metastatic niche during breast cancer.

Microenvironmental changes in the early metastatic niche may be exploited to identify therapeutic targets to inhibit secondary tumor formation and improve disease outcomes. We dissected the developing lung metastatic niche in a model of metastatic, triple-negative breast cancer using single-cell RNA-sequencing. Lungs were extracted from mice at 7-, 14-, or 21days after tumor inoculation corresponding to the pre-metastatic, micro-metastatic, and metastatic niche, respectively. The progression of the metastatic niche was marked by an increase in neutrophil infiltration (5% of cells at day 0 to 81% of cells at day 21) and signaling pathways corresponding to the hallmarks of cancer. Importantly, the pre-metastatic and early metastatic niche were composed of immune cells with an anti-cancer phenotype not traditionally associated with metastatic disease. As expected, the metastatic niche exhibited pro-cancer phenotypes. The transition from anti-cancer to pro-cancer phenotypes was directly associated with neutrophil and monocyte behaviors at these time points. Predicted metabolic, transcription factor, and receptor-ligand signaling suggested that changes in the neutrophils likely induced the transitions in the other immune cells. Conditioned medium generated by cells extracted from the pre-metastatic niche successfully inhibited tumor cell proliferation and migration in vitro and the in vivo depletion of pre-metastatic neutrophils and monocytes worsened survival outcomes, thus validating the anti-cancer phenotype of the developing niche. Genes associated with the early anti-cancer response could act as biomarkers that could serve as targets for the treatment of early metastatic disease. Such therapies have the potential to revolutionize clinical outcomes in metastatic breast cancer.

Understanding the cell survival mechanism of anoikis-resistant cancer cells during different steps of metastasis.

Anchorage-independent survival of cancer cells is associated with metastasis as it enables cells to travel to secondary target sites. Tissue integrity is generally maintained by detachment-induced cell death called 'anoikis', but cancer cells undergoing the multistep metastatic process show resistance to anoikis. Anoikis resistance enables these cells to survive through the extracellular matrix (ECM) deprived phase, which starts when cancer cells detach and move into the circulation till cells reach to the secondary target site. Comprehensive analysis of the molecular and functional biology of anoikis resistance in cancer cells will provide crucial details about cancer metastasis, enabling us to identify novel therapeutic targets against cancer cell dissemination and ultimately secondary tumor formation. This review broadly summarizes recent advances in the understanding of cellular and molecular events leading to anoikis and anoikis resistance. It further elaborates more about the signaling cross-talk in anoikis resistance and its regulation during metastasis.

Abstract 911: Ablation of rare tumor propagating cells during early lung adenocarcinoma development abrogates tumor growth and progression

Abstract Lung cancer is the leading cause of cancer-related death worldwide. Non-small lung cancer accounts for 85% of diagnoses and the predominant subtype is lung adenocarcinoma (LUAD). Previously, we identified a population of Tumor Propagating Cells (TPCs) in the Kras; TP53 GEM model of LUAD. We demonstrated that TPCs have a greater capacity for secondary tumor formation and are enriched after treatment. The TPC population is defined by the expression of CD24, ITGB4 and Notch, with further functional validation showing that Notch3 contributes to this propagation phenotype in a non-redundant fashion. To investigate the biology of these TPCs, we have produced a KrasFSFG12D; Tp53FRT/FRT; Notch3CreERT2; RFP; inducible Diphtheria toxin receptor mouse (KPFFNRiDTR) for lineage tracing and ablation of Notch3 expressing tumor cells to get a granular understanding of the cell types/progeny generated by Notch3 expressing cells and the effects of removing these cells on the tumor microenvironment.In this model, adenovirus expressing FLP is delivered intra-tracheally resulting in expression of an oncogenic form of Kras and deletion of TP53, initiating LUAD tumors. Upon administration of Tamoxifen, Notch3 expressing cells are labelled by induced expression of RFP and DTR, then these cells can be ablated by subsequent dosing with Diphtheria toxin. By labelling/ablating cells at different disease progressions we can infer the importance of Notch signaling at key timepoints and assess the contribution of Notch3 expressing cells to the tumor microenvironment and tumor progression. We have found that Notch3 is expressed in the epithelial progenitors during early embryogenesis up to ~p5 and then gets turned off in the epithelial compartment of distal lung during alveologenesis, and in adults Notch3 is only expressed in the lung pericytes. Thus, the cell of origin for LUAD does not express Notch3, even if the TPC does, and we see the acquisition of Notch3 expression during early tumorigenesis. If we ablate Notch3 positive cells during this state we effectively prevent further growth of the tumors, however we still see similar tumor numbers at endpoint, suggesting that all lesions that will progress are already present when we ablate the TPCs. Considering that the total number of Notch3 cells in the tumor is approximated 1%, this is a profound effect on the overall growth of the tumor and suggests that the TPCs are fundamentally required for lung adenocarcinoma progression and may be a viable target for treatment. Citation Format: Kieren D. Marini, Emma C. Champion, Phuong T. Dinh, Elizabeth E. Hwang, Leanne C. Sayles, E. Alejandro Sweet-Cordero. Ablation of rare tumor propagating cells during early lung adenocarcinoma development abrogates tumor growth and progression [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 911.

Breast cancer progression to other organs

Breast cancer has become very common among women and is the major cause of morbidity. The progression of breast cancer and the formation of secondary tumors in other organs is of major concern. Relapse and recurrence of breast cancer worsen the situation. Multiple genes get altered facilitating metastasis of cancer and downregulation/upregulation of many genes causes variations in molecular expression leading to progression in breast cancer cells. Mainly subtypes of breast cancer are distinct in the expression of hormone receptors (HR) and other proteins like ER, PR, HER2. Breast cancer can invade distant organs commonly in the bone, brain, lung, liver, and also the local region like the chest wall, and lymph nodes. Understanding the mechanism of cancer progression and molecules involved in breast cancer will help in developing therapies to prevent metastasis and find cures for breast cancer. In this review, the biomolecules such as ER, PR, HER2, etc. and the genes involved in breast cancer during its progression, and the mechanisms involved in metastasis have been discussed.

Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma

BackgroundHuman epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem....

Mg-based materials diminish tumor spreading and cancer metastases.

Cancer metastases are the most common causes of cancer-related deaths. The formation of secondary tumors at different sites in the human body can impair multiple organ function and dramatically decrease the survival of the patients. In this stage, it is difficulty to treat tumor growth and spreading due to arising therapy resistances. Therefore, it is important to prevent cancer metastases and to increase subsequent cancer therapy success. Cancer metastases are conventionally treated with radiation or chemotherapy. However, these treatments elicit lots of side effects, wherefore novel local treatment approaches are currently discussed. Recent studies already showed anticancer activity of specially designed degradable magnesium (Mg) alloys by reducing the cancer cell proliferation. In this work, we investigated the impact of these Mg-based materials on different steps of the metastatic cascade including cancer cell migration, invasion, and cancer-induced angiogenesis. Both, Mg and Mg–6Ag reduced cell migration and invasion of osteosarcoma cells in coculture with fibroblasts. Furthermore, the Mg-based materials used in this study diminished the cancer-induced angiogenesis. Endothelial cells incubated with conditioned media obtained from these Mg and Mg–6Ag showed a reduced cell layer permeability, a reduced proliferation and inhibited cell migration. The tube formation as a last step of angiogenesis was stimulated with the presence of Mg under normoxia and diminished under hypoxia.

The Role of SDF‐1 in Signaling Differences Between CXCR4 and Atypical ACKR3 Chemokine Receptors

SDF‐1 is a ligand that plays a critical role in cancer metastases and is secreted in specialized somatic cells in the body. Its chemoattractant properties attract and induce migration of tumor cells located in other tissues in the body to the site in which SDF‐1 is secreted. This attraction and migration of tumor cells allows a new tumor to form at secondary locations within the body. Although the understanding of the function of SDF‐1 being secreted in certain regions of the body is not clear, we seek to understand the binding patterns of this ligand with its chemokine receptors CXCR4 and ACKR3 (also called CXCR7). Chemokine receptors are a subclass of G‐protein coupled receptors, which are multi‐pass transmembrane proteins with 7 TM domains. GPCR activation initiates signaling cascades within the targeted cell. Understanding which signaling pathway is favored in CXCR4 and ACKR3 can help us understand the function of SDF‐1 and the mechanism of secondary tumor formation and development. ACKR3 is considered an atypical receptor as it has been experimentally shown to not couple to Gi/o protein in many cells whereas CXCR4 can couple to either Gi/oprotein or β‐arrestin. ACKR3 strongly binds to SDF‐1 and can control the local levels of SDF‐1 available for binding to CXCR4. Both receptors can couple to β‐arrestins, which are proteins responsible for receptor internalization and potential G‐protein‐independent signaling. To understand the interplay between these two receptors in the context of their interactions with SDF‐1, Gi protein, and β‐arrestin, we have successfully generated structural models of these two receptors in apo form, as heterodimers (bound to only SDF‐1, only Gi protein, or only β‐arrestin), and as heterotrimers (bound to both SDF‐1 and Gi protein, or both SDF‐1 and β‐arrestin). These structural models have been relaxed in their physiological environment using a series of molecular dynamics (MD) simulations. Binding free energy analysis of the heterodimers is beginning to shed light on the signaling differences between the two receptors, what identifies ACKR3 as an atypical receptor, and how it sequesters excess SDF‐1 to modulate CXCR4 signaling.