Stromal Components Research Articles

Tubular Adenoma of the Breast: Radiologic-Pathologic Correlation.

Breast tubular adenomas (TAs) are rare, benign glandular epithelial tumors that arise from a proliferation of acini in the terminal duct lobular units. In the literature, 40 TA cases have previously been reported, and we describe 5 additional cases in this article. In the small number of reported cases, TAs present most often in women of reproductive age but may also occur in postmenopausal women. Mammographically and sonographically, TAs are almost indistinguishable from fibroadenomas (FAs), and they typically present on US as hypoechoic, oval, circumscribed, parallel masses with variable internal vascularity. TAs can also be seen on mammography as oval masses with microlobulated margins, or as grouped coarse, heterogeneous microcalcifications with or without associated mass or asymmetry. On MRI, TAs present as heterogeneously enhancing, T2-hyperintense oval masses with persistent kinetics. Histopathologically, TAs consist of closely packed round tubules with minimal stroma, in distinction to FAs, which have a prominent stromal component that surrounds and can distort the associated tubules. Because of their benign classification and excellent prognosis, patients with biopsy-confirmed TAs may resume routine screening. Complete surgical excision may be considered for cosmetic purposes or for TAs exhibiting associated suspicious calcifications or rapid growth.

PARENCHYMATOUS-STROMAL RATIO IN COLORECTAL CANCER TUMORS AS AN INDICATOR OF METASTASIS

Relevance: Colorectal cancer (CRC) is one of the five most common cancers worldwide and is characterized by trends in incidence, disability, and mortality. A significant recurrence rate and early metastasis characterize CRC. Many meta-analyses in the world literature are aimed at finding factors that determine the probable outcome of the disease.
 The study aimed to evaluate the role of the parenchymal-stromal ratio in the progression of colorectal cancer.
 Methods: When microcopying at 40x magnification, the parenchyma (Sp) and stroma (Sm) area were measured in the areas of superficial tumor growth and deep invasion. The parenchymal-stromal ratio (PSR) was calculated using the formula PSS=Sp/Sm, and the correlation with tumor metastasis was determined.
 Results: With an increase in the depth of tumor invasion, the frequency of metastasis to the liver also increased. The metastasis rate for invasion into the muco-submucosal layer (T1) and the muscular layer (T2) was 4%, respectively. The rate increased to 80% with the involvement of the subserous membrane (T3). Metastases in regional lymph nodes worsened the outcome of the disease threefold. With locally widespread and locally regional in the zone of deep invasion, the parenchymal component predominates over the stroma. PSS is 2.5:1.0 and 1.6:1.0. With CRC disseminated growth in the zone of deep tumor invasion, PSS was 1.0:1.4 with a predominance of the stromal component up to 57%.
 Conclusion: There is a decrease in PSS in superficial growth zones in disseminated forms of colorectal cancer compared with local and local-regional types of cancer. The predominance of the stromal component in the zone of deep invasion is directly proportional to the high adverse outcome.

Immune response and mesenchymal transition of papillary thyroid carcinoma reflected in ultrasonography features assessed by radiologists and deep learning

IntroductionUltrasonography (US) features of papillary thyroid cancers (PTCs) are used to select nodules for biopsy due to their association with tumor behavior. However, the molecular biological mechanisms that lead to the characteristic US features of PTCs are largely unknown. ObjectivesThis study aimed to investigate the molecular biological mechanisms behind US features assessed by radiologists and three convolutional neural networks (CNN) through transcriptome analysis. MethodsTranscriptome data from 273 PTC tissue samples were generated and differentially expressed genes (DEGs) were identified according to US feature. Pathway enrichment analyses were also conducted by gene set enrichment analysis (GSEA) and ClusterProfiler according to assessments made by radiologists and three CNNs - CNN1 (ResNet50), CNN2 (ResNet101) and CNN3 (VGG16). Signature gene scores for PTCs were calculated by single-sample GSEA (ssGSEA). ResultsIndividual suspicious US features consistently suggested an upregulation of genes related to immune response and epithelial-mesenchymal transition (EMT). Likewise, PTCs assessed as positive by radiologists and three CNNs showed the coordinate enrichment of similar gene sets with abundant immune and stromal components. However, PTCs assessed as positive by radiologists had the highest number of DEGs, and those assessed as positive by CNN3 had more diverse DEGs and gene sets compared to CNN1 or CNN2. The percentage of PTCs assessed as positive or negative concordantly by radiologists and three CNNs was 85.6% (231/273) and 7.1% (3/273), respectively. ConclusionUS features assessed by radiologists and CNNs revealed molecular biologic features and tumor microenvironment in PTCs.

Investigating the prognostic value of constructing disulfidptosis-related gene models for lung adenocarcinoma patients.

Disulfidptosis is a novel mode of cell death, a programmed mode of intracellular disulfide accumulation due to solute carrier family 7 member 11 (SLC7A11)-mediated abnormalities in the cell membrane cystine transport system. Numerous studies have confirmed the prominent role played by SLC7A11 in tumors, but the involvement of SLC7A11 as an important mediator of disulfidptosis in the death process of lung adenocarcinoma cells remains unclear. We obtained 4,107 SLC7A11-related genes and analyzed them using a total of 1,040 lung adenocarcinoma transcriptome sequencing data from The Cancer Genome Atlas (TCGA) cohort and GEO (Gene Expression Omnibus) cohort and 991 relevant clinical data. First, we screened for differential genes and identified molecular subtypes for assessing characteristic differences between lung adenocarcinoma subtypes under the influence of SLC7A11-associated genes. Then, risk score models were constructed to assess the prognosis, immune infiltration, tumor microenvironment, and drug treatment effects in lung adenocarcinoma patients. Finally, we also analyzed the distribution of cell types and expression of characteristic genes within the tumor using a single-cell database. In addition, relevant drug sensitivities were predicted. We screened 956 genes with significant differences and identified 2 molecular subtypes and found significant differences in their prognosis and that subtype B had a significantly better survival prognosis than subtype A. In addition, we found that pathways associated with cell proliferation division and DNA repair were enriched in the high-risk type A samples. Finally, we constructed a robust risk-scoring system, and our risk analysis revealed a general reduction of various immune cell components and tumor stromal components in the immune microenvironment of high-risk lung adenocarcinoma and a distinct immune infiltration pattern of immune cells, which was associated with a lower survival rate. Our comprehensive analysis of SLC7A11-related genes suggests that disulfidptosis has a potential value in the tumor microenvironment, immunity, clinical outcome, and prognosis of lung adenocarcinoma. These findings may increase our understanding of disulfidptosis as a novel cell death paradigm and provide ideas for assessing the prognosis of lung adenocarcinoma and developing new diagnostic and therapeutic strategies.

Fungal Keratitis. Part 1. Etiomorphology, Historical Aspects, Epidemiology, Risk Factors, Pathogenesis and Clinical Features

Fungal keratitis (FK) is 8–30 % in the structure of infectious inflammation of the cornea. There are 2 main types of mushroom growth — mycelial and yeast. Mycelial (mold) fungi grow in the form of special branched microscopic tubes — hyphae. Yeast fungi form compact colonies of individual oval cells. Due to the peculiarities of the yeast structure, the tendency to rapid spread in the tissues is reduced, which determines the less aggressive clinical course of such keratomycosis compared to mold. Until the 50s of the 20th century, the occurrence of FK in the world was low. However, probably with the introduction of corticosteroid and antibacterial drugs into medicine, their prevalence began to grow. The highest frequency of occurrence of FK is in regions with a hot climate and high involvement of the population in agriculture. The main provoking factor for the appearance of FK is corneal injury with damage to the epithelium and adhesion to the Bowman’s membrane or stroma components. Highly adhesive fungi (Aspergillus spp., Candida spp.) trigger a cascade of immune inflammatory reactions, production of reactive oxygen species and matrix metalloproteases-9, which leads to the destruction of lamellae. Fungi with low adhesive ability (Fusarium spp.) can grow parallel to lamellae for a long time and indefinitely without inducing pronounced inflammation. Symptoms of FC are similar to those observed in other forms of infectious keratitis, but more often they develop more slowly (5–10 days) and are less acute. A defect against the background of mycelial FC is more often characterized by jagged edges, a raised slough, and a non-yellow color. Yeast FK is manifested by oval ulceration of the epithelium with expanding, more sharply demarcated, densely focal suppuration.

Integrating single-cell and spatial transcriptomics reveals endoplasmic reticulum stress-related CAF subpopulations associated with chordoma progression.

With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.

Next-Generation Sequencing Analysis of 3 Uterine Adenosarcomas with Heterogeneously Differentiated Genomic Mutations.

Uterine adenosarcoma (UA) is an uncommon mixed tumor containing a benign to at most mildly atypical epithelial component and a sarcoma-like stroma, usually a low-grade, stromal component, with rare heterogeneous elements. Currently, tumor etiology is largely unknown. To better understand the gene mutations in UA, next-generation sequencing (NGS) technology analysis was performed. This study showed that two low-grade UAs with heterologous components had ATRX gene frameshift mutation, and one patient had a MED12 missense mutation. Copy number amplification genes were mainly observed on chromosome 12q13-15. In this study, PIK3/AKT/PTEN pathway mutations were found to be common in adenosarcoma. In addition, a rare BCORL1-PRR14L fusion mutation was also identified. These findings provide a basis for future research into these molecular changes in tumorigenesis and targeted therapy.

Clinicopathological Parameters Predicting Malignancy in Phyllodes Tumor of the Breast.

Introduction Phyllodes tumor (PT) is an uncommon fibroepithelial neoplasm of the breast. It is a biphasic tumor with stromal and epithelial components, with a tendency to recur. Because of its wide range of disease manifestations, it has been subclassified into three categories, i.e., benign, borderline, and malignant, based on several histological parameters. This study was conducted to evaluate the clinicopathological features associated with malignancy in breast PTs. Methods We conducted a retrospective study at the Department of Histopathology at Liaquat National Hospital, Karachi, Pakistan. A total of 146 biopsy-proven cases of PTs were enrolled in the study. Clinical data were obtained from the clinical referral forms. Specimens were obtained from either lumpectomy or simple mastectomy. The specimens obtained were received at the laboratory where after gross examination, paraffin-embedded tissue blocks were prepared, which were sectioned, stained, and studied by a senior histopathologist. Pathological features, such as mitotic count, necrosis, stromal atypia, stromal overgrowth, and heterologous elements, were observed. Based on these features, the PTs were classified into benign, borderline, and malignant tumors. Results The mean age of the PTs in our setup was 40.65 ± 12.17 years with a mean size of 9.40 ± 6.49 cm. Malignant PT was found to be the most prevalent in our population, accounting for 63 (43.2%) cases, followed by borderline (51, 34.9%) and benign (32, 21.9%). A significant association was found between the tumor subtype and patient age, i.e., patients diagnosed with malignant and borderline PTs were found to be of older age (mean 42.82 ± 12.94 and 42.05 ± 11.31 years, respectively) than those diagnosed with benign PTs (mean age 34.12 ± 9.75 years). Moreover, malignant PTs were associated with larger tumor size (mean 11.46 ± 6.08) compared with the other two subtypes. Conclusion We found a significant association among patient age, tumor size, and PT subtype. Therefore, apart from the usual histological parameters, patient age and tumor sizeare important parameters for predicting the behavior of breast PT and should be considered for management.

A prospective comparative study of preoperative and postoperative clinicopathological correlation of fibroadenoma of breast: A study protocol

Fibroadenoma of the breast most often arises during the late teens and early reproductive years. It is the most prevalent tumor in women < 30 years. After the age of 40 to 45, fibroadenomas are rarely observed as new masses in women. Fibroadenomas are made up of both epithelial and stromal components. Fibroadenoma is the most frequent type of breast tumor. It is crucial to diagnose preoperatively, both clinically and pathologically, by using F.N.A.C. Postoperatively, Fibroadenoma is confirmed histopathology. However, malignant transformation is very rare in Fibroadenoma of the breast. Early identification, accurate analysis, and appropriate management are advantageous. The current study's goal is to examine preoperative and postoperative clinicopathological aspects of Fibroadenoma and to assess any differences between preoperative and postoperative diagnosis in patients admitted to Jawaharlal Nehru Medical College, Sawangi (M), Wardha, Maharashtra, India.

Application of organoids in precision immunotherapy of lung cancer (Review).

In immunotherapy, the immune system is modulated in order to treat cancer. Traditional two dimensional in vitro models and in vivo animal models are insufficient to simulate the complex tumor microenvironment (TME) in the original tumor. As tumor immunotherapy involves the immune system, additional tumor mimic models, such as patient-derived organoids, are required for the evaluation of the efficacy of immunotherapy. Furthermore, non-tumor components and host tumor cells in the TME may interact to promote cancer incidence, progression, drug resistance and metastasis. It is possible to produce organoid models for lung cancer by retaining endogenous stromal components (e.g., multiple immune cell types), supplying cancer-associated fibroblasts and exogenous immune cells, constructing tumor vasculature and adding other biological or chemical components that emulate the TME. Therefore, the lung cancer organoid culture platform may facilitate preclinical testing of immunotherapy drugs for lung cancer by mimicking immunotherapy responses. The present review summarizes current lung cancer organoid culture methods for TME modeling and discusses the use of lung cancer-derived organoids for the detection of lung cancer immunotherapy and individualized cancer immunotherapy.

Immunohistochemical and ultrastructural identification of telocytes in the lamina propria of human vaginal mucosa

Since their relatively recent discovery, telocytes (TCs) have been described as peculiar cells strategically positioned in the stromal tissue component of multiple organ systems of the mammalian body including female reproductive organs (i.e., ovary, uterine tube, and uterus). Nevertheless, current knowledge of TCs in the vagina is very limited. The present study was therefore undertaken to investigate the existence and characteristics of TCs in the stromal tissue of human vaginal mucosa by means of immunohistochemistry, immunofluorescence confocal microscopy, and transmission electron microscopy. In the vaginal lamina propria, TCs were first identified by CD34 immunohistochemistry that revealed the presence of CD34+ stromal cells arranged in networks, especially around blood vessels. Double immunofluorescence confocal microscopy allowed to precisely distinguish the perivascular networks of CD34+ stromal cells lacking CD31 immunoreactivity from adjacent CD31+ microvessels. All the perivascular networks of TCs/CD34+ stromal cells situated in the vaginal lamina propria coexpressed platelet-derived growth factor receptor α, which strengthened their identification as TCs. Instead, vaginal mucosal TCs were immunophenotypically negative for c-kit/CD117. The ultrastructural examination confirmed the presence of TCs, namely stromal cells with characteristic cytoplasmic processes (i.e., telopodes) forming labyrinthine networks around blood vessels and releasing extracellular vesicles. Together, our morphological findings provide the first comprehensive demonstration that TCs reside in the human vaginal lamina propria, thus paving the way for further investigation of their putative functions in vaginal mucosal homeostasis and pathophysiology.

Prognostic biomarker SYK and its correlation with immune infiltrates in glioma.

The tumor microenvironment (TME) provides excellent conditions for the development of glioma. The present study sought to identify the prognostic factors of glioma that could be used to improve the prognosis of patients with this disease. In the present study, Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data calculations were employed to estimate the ratio of tumor-infiltrating immune cells and the quantity of immune and stromal components in 698 glioma cases from the Cancer Genome Atlas database. In addition, certain differentially expressed genes were studied by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and single genes associated with prognosis were identified by protein-protein interaction (PPI) network and Cox combined analysis. The immune and stromal scores of the TME were significantly associated with glioma patient survival. By using the PPI network and Cox regression analyses, spleen tyrosine kinase (SYK) was eventually identified as the best prognostic factor for patients with glioma. In addition, Gene Set Enrichment Analysis and CIBERSORT analyses were employed. The former indicated that the high-expression SYK group genes were mainly enriched in immune-related activities. The latter revealed that SYK expression was positively associated with T cell cluster of differentiation 4 memory resting and monocytes. The aforementioned experimental analyses provided the theoretical basis for the biological prediction of SYK. The data indicated that SYK contributed to immune predictors in patients with glioma by facilitating the shift of the TME from immune dominance to metabolic activity. Finally, reverse transcription-quantitative PCR and western blotting were used to verify the single gene expression in glioma cells. This may provide prognostic value for the treatment of glioma.

Molecular and immunological mechanisms of clonal evolution in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages.

Receptive status of the endometrium in patients of reproductive age with serous and mucinous ovarian cystadenoma before and after unilateral adnexectomy

BACKGROUND: Currently, the incidence of benign ovarian tumors has increased, and numerous studies have reported its negative effect on womens reproductive health. In modern literature, approximately 30% of patients with ovarian neoplasms have reproductive problems. In the presence of ovarian diseases, changes in the endometrium alter its receptivity, thereby reducing the chances of successful conception and gestation and gaining increasing attention. Patients seeking to preserve their reproductive function prefer organ-preserving surgical interventions; however, in clinical practice, adnexectomy is often necessary because of damaged ovarian tissue.
 AIM: To analyze the morphofunctional state of the endometrium and its receptivity in patients with serous and mucinous ovarian cystadenomas before and after surgical treatment.
 MATERIALS AND METHODS: The prospective study included patients of reproductive age with benign epithelial tumors (serous/mucinous cystadenomas) who had not received hormonal drugs for 6 months before surgical treatment. Group 1 included 32 patients with serous cystadenoma, and group 2 included 30 patients with mucinous cystadenoma. Before and 612 months after unilateral salpingo-oophorectomy, a pipelle biopsy of the endometrium was performed during the implantation window. The qualitative and quantitative parameters of pinopodes were examined, and the expression levels of estrogen (ER) and progesterone (PR) receptors in the glands and stroma of the endometrium were evaluated.
 RESULTS: Preoperatively, the number of pinopodes decreased in patients with serous cystadenoma, and the expression level of ER in the stroma and those of PR in the stroma and glands was reduced. Postoperatively, the number of mature pinopodes increased, and the expression levels of ER in the stroma and PR in the stroma and glands was increasing. Preoperatively, in patients with mucinous cystadenomas, the expression levels of ER in the stroma and glands and PR in the stroma and glands decreased, and the number of pinopodes reduced. Postoperatively, compared with patients with serous cystadenomas in the glandular component of the endometrium, those with mucinous cystadenoma had lower expression levels of both ER and PR, lower PR expression level in the stromal component, and increased number of pinopodes.
 CONCLUSIONS: The results of this study showed that benign ovarian tumors are accompanied by impaired morphofunctional state and receptivity of the endometrium, and timely surgical intervention positively affects these indicators and increases the reproductive potential of women.

Cancer-associated fibroblasts: Just on the opposite side of antitumour immunity?

The tumour microenvironment (TME) is critical for the initiation, progression, and metastasis of tumours, and cancer-associated fibroblasts (CAFs) are the most dominant cells and have attracted interest as targets for cancer therapy among the stromal components within the TME. Currently, most of the identified CAF subpopulations are believed to exhibit suppressive effects on antitumour immunity. However, accumulating evidence indicates the presence of immunostimulatory CAF subpopulations, which play an important role in the maintenance and amplification of antitumour immunity, in the TME. Undoubtedly, these findings provide novel insights into CAF heterogeneity. Herein, we focus on summarizing CAF subpopulations that promote antitumour immunity, the surface markers of these populations, and possible immunostimulatory mechanisms in the context of recent advances in research on CAF subpopulations. In addition, we discuss the possibility of new therapies targeting CAF subpopulations and conclude with a brief description of some prospective avenues for CAF research.

Suppressive stroma-immune prognostic signature impedes immunotherapy in ovarian cancer and can be reversed by PDGFRB inhibitors

BackgroundAs the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy.MethodsThe 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature.ResultsThe SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs’ marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer.ConclusionsThe stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer.

HAPLN1 matrikine: a bone marrow homing factor linked to poor outcomes in patients with MM

AbstractThe bone marrow (BM) microenvironment is critical for dissemination, growth, and survival of multiple myeloma (MM) cells. Homing of myeloma cells to the BM niche is a crucial step in MM dissemination, but the mechanisms involved are incompletely understood. In particular, any role of matrikines, neofunctional peptides derived from extracellular matrix proteins, remains unknown. Here, we report that a matrikine derived from hyaluronan and proteoglycan link protein 1 (HAPLN1) induces MM cell adhesion to the BM stromal components, such as fibronectin, endothelial cells, and stromal cells and, furthermore, induces their chemotactic and chemokinetic migration. In a mouse xenograft model, we show that MM cells preferentially home to HAPLN1 matrikine–conditioned BM. The transcription factor STAT1 is activated by HAPLN1 matrikine and is necessary to induce MM cell adhesion, migration, migration-related genes, and BM homing. STAT1 activation is mediated by interferon beta (IFN-β), which is induced by NF-κB after stimulation by HAPLN1 matrikine. Finally, we also provide evidence that higher levels of HAPLN1 in BM samples correlate with poorer progression-free survival of patients with newly diagnosed MM. These data reveal that a matrikine present in the BM microenvironment acts as a chemoattractant, plays an important role in BM homing of MM cells via NF-κB–IFN-β–STAT1 signaling, and may help identify patients with poor outcomes. This study also provides a mechanistic rationale for targeting HAPLN1 matrikine in MM therapy.

Role of the tumor microenvironment in the lymphatic metastasis of cervical cancer (Review).

Lymphatic metastasis is the primary type of cervical cancer metastasis and is associated with an extremely poor prognosis in patients. The tumor microenvironment primarily includes cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, immune and inflammatory cells, and blood and lymphatic vascular networks, which can promote the establishment of lymphatic metastatic sites within immunosuppressive microenvironments or promote lymphatic metastasis by stimulating lymphangiogenesis and epithelial-mesenchymal transformation. As the most important feature of the tumor microenvironment, hypoxia plays an essential role in lymph node metastasis. In this review, the known mechanisms of hypoxia, and the involvement of stromal components and immune inflammatory cells in the tumor microenvironment of lymphatic metastasis of cervical cancer are discussed. Additionally, a summary of the clinical trials targeting the tumor microenvironment for the treatment of cervical cancer is provided, emphasizing the potential and challenges of immunotherapy.

Increased RUNX3 expression mediates tumor-promoting ability of human breast cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) are a major stromal component of human breast cancers and often promote tumor proliferation, progression and malignancy. We previously established an experimental CAF (exp-CAF) cell line equipped with a potent tumor-promoting ability. It was generated through prolonged incubation of immortalized human mammary fibroblasts with human breast cancer cells in a tumor xenograft mouse model. Herein, we found that the exp-CAFs highly express Runt-related transcription factor 3 (RUNX3), while counterpart fibroblasts do not. In breast cancer patients, the proportion of RUNX3-positive stromal fibroblast-like cells tends to be higher in cancerous regions than in non-cancerous regions. These findings suggest an association of RUNX3 with CAF characteristics in human breast cancers. To investigate the functional role of RUNX3 in CAFs, the exp-CAFs with or without shRNA-directed knockdown of RUNX3 were implanted with breast cancer cells subcutaneously in immunodeficient mice. Comparison of the resulting xenograft tumors revealed that tumor growth was significantly attenuated when RUNX3 expression was suppressed in the fibroblasts. Consistently, Ki-67 and CD31 immunohistochemical staining of the tumor sections indicated reduction of cancer cell proliferation and microvessel formation in the tumors formed with the RUNX3-suppressed exp-CAFs. These results suggest that increased RUNX3 expression could contribute to the tumor-promoting ability of CAFs through mediating cancer cell growth and neoangiogenesis in human breast tumors.

Integrative analysis of cancer-associated fibroblast signature in gastric cancer

BackgroundCAFs regulate the signaling of GC cells by promoting their migration, invasion, and proliferation and the function of immune cells as well as their location and migration in the TME by remodeling the extracellular matrix (ECM). This study explored the understanding of the heterogeneity of CAFs in TME and laid the groundwork for GC biomarker and precision treatment development. MethodsThe scRNA-seq and bulk RNA-seq datasets were obtained from GEO and TCGA. The prognostic significance of various CAFs subtypes was investigated using ssGSEA combined with Kaplan-Meier analysis. POSTN expression in GC tissues and CAFs was detected using immunohistochemistry, immunofluorescence, and Western blotting. Differential expression analysis identified the differentially expressed genes (DEGs) between normal and tumor samples in TCGA-STAD. Pearson correlation analysis identified DEGs associated with adverse prognosis CAF subtype, and univariate Cox regression analysis determined prognostic genes associated with CAFs. LASSO regression analysis and Multivariate Cox regression were used to build a prognosis model for CAFs. ResultsWe identified five CAFs subtypes in GC, with the CAF_0 subtype associated with poor prognosis. The abundance of CAF_0 correlated with T stage, clinical stage, histological type, and immune cell infiltration levels. Periostin (POSTN) exhibited increased expression in both GC tissues and CAFs and was linked to poor prognosis in GC patients. Through LASSO and multivariate Cox regression analysis, three genes (CXCR4, MATN3, and KIF24) were selected to create the CAFs-score. We developed a nomogram to facilitate the clinical application of the CAFs-score. Notably, the CAFs signature showed significant correlations with immune cells, stromal components, and immunological scores, suggesting its pivotal role in the tumor microenvironment (TME). Furthermore, CAFs-score demonstrated prognostic value in assessing immunotherapy outcomes, highlighting its potential as a valuable biomarker to guide therapeutic decisions. ConclusionCAF_0 subtype in TME is the cause of poor prognosis in GC patients. Furthermore, CAFs-score constructed from the CAF_0 subtype can be used to determine the clinical prognosis, immune infiltration, clinicopathological characteristics, and assessment of personalized treatment of GC patients.