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Introduction: In squamous cell carcinoma, cells invade the stroma in the form of islands, strands or sheets, which are surrounded by an extracellular matrix, thus producing reactive changes in the stroma. These reactive changes in the stroma may alter the biological behavior of oral cancer which convey some diagnostic and prognostic significance. Objective: This study was to compare staining intensity of various components of connective tissue such as collagen, elastin and glycoprotein among three histological grades of oral squamous cell carcinoma and normal oral mucosa. Materials and Methods: A total sample of 48 in which 36 cases of histologically diagnosed oral squamous cell carcinoma, 12 each of well, moderate and poorly differentiated squamous cell carcinomas and 12 sections of normal mucosa as the control group were selected for the present study. The sections of tissue blocks were stained with connective tissue specific stains such as Verhoeff’s -VanGieson stain and PAS for collagen, elastin and glycoprotein respectively. Results: Staining intensity of collagen, elastin and glycoprotein around tumor island among different grades of OSCC and normal mucosa revealed statistically significant changes (P value <0.001). Collagen and glycoprotein degradation and elastosis are more prominent in poorly differentiated squamous cell carcinomas. Conclusion: Observable changes were seen in the stroma, in all the three grades of OSCC’s compared to normal mucosa. There was an increased stromal response in poorly differentiated carcinomas, when compared to the other grades. Role of the stroma is like a double-edged sword, at times helping in tumor invasion and otherwise warding off the tumor cells.
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The main components of the gastric tumor stroma consist of cells in both the immune and non-immune microenvironments. The effectiveness of a series of therapeutic measures such as adjuvant chemotherapy is closely related to the composition of gastric tumor stroma. By analyzing the components in the gastric tumor stroma, we understand the characteristics of the constituents in the pathological structure of gastric cancer, and further explore the connection of each component of the stroma with pathological structure and regulatory mechanisms of stroma components on the occurrence and progression of gastric tumors. Combined with artificial intel-ligence technology to analyze the pathological features related to stroma components of tumor microenvironment, the dynamic changes of immune microenvironment and non-immune microen-vironment in gastric cancer are expected to reveal.
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Objective:To explore the value of tumor stroma ratio (TSR) in non-small lung cancer (NSCLC) tissue in predicting the efficacy of tumor immunotherapy.Methods:The clinical and histopathological data of patients with stage ⅢB-Ⅳ NSCLC treated with immune checkpoint inhibitors in the Renmin Hospital of Wuhan University from January 2017 to December 2020 were collected. Taking 50% as the TSR boundary value, the patients were divided into low TSR group (≤50%) and high TSR group (>50%) . The histopathological features, 4-cycle objective response rate (ORR) and disease control rate (DCR) , 6-cycle ORR and DCR, and progression-free survival (PFS) were compared between the two groups. Univariate and multivariate Cox regression models were used to analyze the prognostic factors related to PFS.Results:A total of 50 patients were included, including 27 with low TSR and 23 with high TSR. There were no significant differences between the two groups in age ( χ2=0.59, P=0.441) , gender ( P=0.578) , smoking history ( χ2=0.12, P=0.730) , histopathological type ( χ2=2.33, P=0.313) , TNM stage ( χ2=0.22, P=0.636) , 4-cycle ORR ( χ2=0.48, P=0.487) and DCR ( P=0.593) , 6-cycle ORR ( χ2=0.05, P=0.818) and DCR ( P=0.641) . The incidence of brain metastasis was higher in the high TSR group than that in the low TSR group [34.8% (8/23) vs. 7.4% (2/27) , χ2=4.23, P=0.040]. Kaplan-Meier survival analysis showed that the PFS in the low TSR group was significantly longer than that in the high TSR group (15.6 months vs. 10.2 months, χ2=13.84, P<0.001) . Univariate analysis showed that TSR value ( HR=0.29, 95% CI: 0.14-0.58, P<0.001) and brain metastasis ( HR=2.38, 95% CI: 1.12-5.05, P=0.024) were correlated with the worse prognosis of NSCLC patients. Multivariate Cox regression analysis showed that TSR value was an independent prognostic factor for NSCLC immunotherapy ( HR=0.32, 95% CI: 0.14-0.70, P=0.004) . Conclusion:TSR is an independent predictor of immunotherapy for NSCLC, but whether it can predict the short-term efficacy of immunotherapy for advanced NSCLC still needs further research.
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ABSTRACT Background: Cancer gene therapy using a nonviral vector is expected to be repeatable, safe, and inexpensive, and to have long-term effectiveness. Gene therapy using the E3 and C1 (E3C1) domain of developmental endothelial locus-1 (Del1) has been shown to improve prognosis in a mouse transplanted tumor model. Objective: In this study, we examined how this treatment affects angiogenesis in mouse transplanted tumors. Materials and methods: Mouse transplanted tumors (SCCKN human squamous carcinoma cell line) were injected locally with a nonviral plasmid vector encoding E3C1 weekly. Histochemical analysis of the transplanted tumors was then performed to assess the effects of E3C1 on prognosis. Results: All mice in the control group had died or reached an endpoint within 39 days. In contrast, one of ten mice in the E3C1 group had died by day 39, and eight of ten had died or reached an endpoint by day 120 (p < 0.01). Enhanced apoptosis in tumor stroma was seen on histochemical analyses, as was inhibited tumor angiogenesis in E3C1-treated mice. In addition, western blot analysis showed decreases in active Notch and HEY1 proteins. Conclusion: These findings indicate that cancer gene therapy using a nonviral vector encoding E3C1 significantly improved life-span by inhibiting tumor angiogenesis. (REV INVEST CLIN. 2021;73(1):39-51)
Subject(s)
Animals , Rabbits , Calcium-Binding Proteins/therapeutic use , Carcinoma, Squamous Cell/blood supply , Carcinoma, Squamous Cell/therapy , Cell Adhesion Molecules/therapeutic use , Epidermal Growth Factor/therapeutic use , Discoidin Domain/genetics , Calcium-Binding Proteins/genetics , Tumor Cells, Cultured , Genetic Therapy , Cell Adhesion Molecules/genetics , Amino Acid Motifs , Epidermal Growth Factor/genetics , Mice, Nude , Neoplasm Transplantation , Neovascularization, Pathologic/therapyABSTRACT
The administration of nanoparticles (NPs) first faces the challenges of evading renal filtration and clearance of reticuloendothelial system (RES). After that, NPs infiltrate through the expanded endothelial space and penetrated the dense stroma of tumor microenvironment to tumor cells. As long as possible to prolong the time of NPs remaining in tumor tissue, NPs release active agent and induce pharmacological action. This review provides a comprehensive summary of the physical and chemical properties of NPs and the influence of various biological factors in tumor microenvironment, and discusses how to improve the final efficacy through adjusting the characteristics and structure of NPs. Perspectives and future directions are also provided.
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Objective:To develop and validate a radiomics biomarker for the preoperative estimation of the tumor-stroma ratio (TSR) in rectal cancer.Methods:From January 2016 to March 2019, totally 149 patients with rectal cancer were enrolled retrospectively at Fudan University Shanghai Cancer Center. The patients were divided into two cohorts using a random number table, 119 in the training and 30 in validation cohorts. The patients were classified into the TSR-high group (TSR>50%) and TSR-low group (TSR≤50%) according to the content of tumor stroma in pathology. All patients underwent T 2WI, enhanced T 1WI and DWI. The lesions on the T 2WI, enhanced T 1WI, DWI and ADC images were delineated and radiomics features were extracted. A radiomics signature (rad-score) was generated by using the least absolute shrinkage and selection operator (LASSO) algorithm. The Spearman correlation coefficients were used to determine the association between rad-score and TSR. The area under the ROC curve (AUC) was used to assess the diagnostic performance of the rad-score. The reliability of the rad-score was quantified by calculating the sensitivity, specificity and accuracy of TSR. Results:With LASSO, a rad-score with 13 radiomics parameters was successfully constructed and was positively correlated with TSR score in the training ( r=0.72, P<0.001) and validation cohorts ( r=0.46, P=0.011). In the training cohort, the AUC of the rad-score was 0.940, with the sensitivity, specificity, accuracy of 100%, 87.3%, 92.4%. In the validation cohort, the AUC was 0.796, with the sensitivity, specificity, accuracy of 83.3%, 67.7%, 73.3%. Conclusions:The rad-score is of promising value for TSR estimation in rectal cancer. It is a promising supplement for patient stratification and may inform decision-making.
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Introduction: Several studies regarding tumor-stroma ratio (TSR) in colorectal, esophageal, breast, endometrial, and cervical carcinomas have been done in the past with significant results. Objectives: The objectives of this study were to (1) study and grade TSR in buccal mucosa and tongue squamous cell carcinoma (SCC), (2) grade inflammatory cell infiltrate surrounding the tumor, and (3) correlate the above two parameters with tumor grade, lymph node metastasis, lymphovascular invasion (LVI), and perineural invasion (PNI). Materials and Methods: Totally, 25 patients of buccal SCC and 16 cases of tongue SCC were included in the study. TSR was assessed visually on the hematoxylin and eosin-stained tissue sections by two independent observers. Cases were categorized into two groups: One with high TSR >50% (stroma poor) and the other with low TSR <50% as the stroma-rich group. TSR was correlated with tumor size, lymph node metastasis, inflammatory cell infiltrate, LVI, and PNI. Data were analyzed by the Statistical Package for the Social Sciences version 16.0 (Chicago, IL, USA) for Windows. The Chi-square and Fischer's exact tests were applied in the analysis of categorical variable. Results and Conclusion: SCC of buccal mucosa showed a significant correlation between TSR and size of the tumor (P = 0.001). We found that smaller the tumor size ≤2 cm (Stage T1), lesser the TSR, and size >2 cm was found to be associated with higher TSR. Hence, higher TSR (stroma poor) was associated with an adverse pathological characteristic, i.e., advanced T significantly. There was no significant correlation between TSR and inflammatory infiltrate with grade of the tumor, lymph node metastasis, LVI, and PNI. In 16 cases of SCC of the tongue; no correlation was observed between TSR and inflammatory infiltrate with tumor size, grade of the tumor, lymph node metastasis, LVI, and PNI. TSR has been studied in various malignancies (mostly adenocarcinomas) including laryngeal SCCs; however, it has never been studied on oral SCCs
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Aims and Objectives: We examined the prognostic value of Tumor stroma ratio (TSR) in breast tumor core biopsy (TCB) specimen to determine response to neoadjuvant therapy (NAT) prior to modified radical mastectomy (MRM). Methods: This was a retrospective analysis of patients with breast cancer who underwent TCB before NAT between August 2016 and July 2018. TSR in TCB was studied independently by 2 pathologists ( VM, VS) defined as stroma rich (TSR?50%) or stroma poor (TSR>50%). MRM specimen of these patients were subsequently studied .Residual cancer burden (RCB) was calculated using the MD Anderson RCB calculator, categorized as complete (0), good (1) Partial (2) and no response (3). Statistical analysis was done to assess correlation of TSR to RCB. Results: A total of 62 patients were analyzed. Mean(SD) age was 48(11) years.Twenty eight (45%) and 34 (55%) patients were stroma rich and stroma poor respectively. Twenty six (42%) patients were responders and 36 (58%) non-responders to NAT. Among stroma rich patients, only 3 (10%) were responders (Class 0 &1)and 25 (90%) non-responders(Class2&3)to NAT, among stroma poor patients 23 (68%) responded well and 11 (32%) did not.TSR had a moderate negative correlation with RCB (-0.6). On univariate analysis, only TSR had a significant effect on RCB class (<0.001). Conclusions: TSR on TCB is a useful prognostic factor to determine response of breast carcinoma patients to neoadjuvant therapy.It is cost effective, simple and quick. Larger multi-centric studies would be useful to study its clinical implications.
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ObjectiveTo investigate the effect of tumor-stroma crosstalk on amino acid metabolism in hepatic stellate cells (HSCs). MethodsHuman hepatoma cell lines HepG2, Hep3B, and Huh7 and the HSC LX-2 were cultured separately. HSCs were cultured in HSC LX-2 conditioned medium (LX2-CM) and HepG2/Hep3B/Huh7 mixed conditioned medium (Hep-CM), respectively. The supernatants were collected and an amino acid analyzer was used to measure the change in aminogram. The t-test was used for comparison of continuous data between groups. ResultsThere was a significant change in amino acid metabolism in HSCs. Compared with the LX2-CM control group, the Hep-CM experimental group had significant reductions in the levels of citrulline (t=3.426, P=0.027), valine (t=2.892, P=0.045), isoleucine (t=4.224, P=0.013), leucine (t=4.150, P=0.014), tyrosine (t=3556, P=0.024), phenylalanine (t=4.023, P=0.016), and lysine (t=3.369, P=0.028) in cell supernatant. ConclusionTumor-stroma crosstalk can influence amino acid metabolism in HSCs in tumor microenvironment, and such change in turn makes hepatoma cells better adapted to hypoxic microenvironment.
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Presently morphological evaluation and special staining scoring system are important components of basic and clinical research, and are very important for judging the efficacy of drugs and gene intervention. However, the current visual scoring system has some disadvantages such as strong subjectivity, poor repeatability and low accuracy, and is prone to missed diagnosis and misdiagnosis. Artificial intelligence technology based on deep learning is expected to overcome these problems. In our study, we found that the convolutional neural network can be used to accurately extract internal features related to the treatment and prognosis of tumors, such as tumor-stroma ratio, nerve invasion and spatial distribution of lymphatic cells in tumor specimens, visualizing and digitalizing the curative effect of drug intervention on disease progression, and can quantify and automatic evaluate the expression of molecular biomarkers related to clinical treatment, classification and prognosis. The application of artificial intelligence technology in tissue and cell morphology assessment will promote the consistency, repeatability and accuracy of clinical drug evaluation and basic scientific research evaluation, and is expected to further promote the development of medical research.
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Objective To investigate the value of tumor-stroma ratio(TSR) in evaluating the prognosis of patients with triple-negative breast cancer (TNBC).Methods A total of 87 patients with TNBC were selected from January 2010 to December 2014 in the Second People's Hospital of Yibin.The TSR was detected by Hematoxylin eosin staining,the patients with TSR ＜50％ were included in the stroma-rich group,and the patients with TSR≥50％ were included in the stroma-rare group.The influencing factors of tumor-free survival and overall survival in TNBC patients were analyzed by COX regression model.The effect of TSR on tumor-free survival and overall survival in TNBC patients was further analyzed by Kaplan-Meier method.Results Among the 87 TNBC patients,there were 38 patients with TSR≥50％ (stroma-rare group) and 49 patients with TSR ＜ 50％ (stroma-rich group).The 5-year tumor-free survival rate and overall survival rate of the 87 TNBC patients was 52.9％ (46/87) and 56.3％ (49/87) respectively.Single factor COX regression analysis showed that the tumor diameter staging,lymph node metastasis,the number of tumors and TSR were significantly correlated with the overall survival rate and tumor-free survival rate of patients with TNBC (P ＜ 0.05).Multivariate COX regression analysis showed that the tumor diameter staging,lymph node metastasis,the number of tumors and TSR were independent risk factors for overall survival rate and tumor-free survival rate of patients with TNBC (P ＜ 0.05).Kaplan-Meier survival analysis showed that the tumor-free survival rate and the overall survival rate of TNBC patients in the stroma-rare group were 68.4％ (26/38) and 73.7％ (28/38),and they were 40.8％ (20/49) and 42.9％ (21/49) in the stroma-rich group.The Log-Rank test showed that the overall survival rate and disease-free survival rate of the TNBC patients in the stroma-rare group were significantly higher than those in the stroma-rich group (x2 =7.788,9.799;P ＜ 0.05).Conclusion TSR is significantly associated with the prognosis of TNBC patients,and it is an independent risk factor for the prognosis of TNBC patients.TSR can be used as an indicator for evaluating the prognosis of TNBC patients.
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Progression of cancer is often associated with interactions between cancer cells and extracellular matrix (ECM) surrounding them. Increasing evidence has suggested that accumulation of hyaluronan (HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized typically by a dense desmoplastic stroma with a large amount of HA, making this molecule as an attractive target for therapy. Several studies have shown efficacy of inhibitors of HA synthesis or signaling for the treatment of PDAC. Recent studies have also demonstrated substantial improvements in the effects of chemotherapy by a targeted depletion of stromal HA in PDAC using an enzymatic agent. Thus, targeting HA has been recognized as a promising therapeutic strategy to treat this highly aggressive neoplasm. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.
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Ovarian cancer bears the highest mortality in gynecologic cancer, and its 5-year survival rate is about 30%. Although 70% to 80% ovarian cancer is epithelial origin, increasing evidence indicates that reciprocal interactions between tumor cells and various types of stromal cells also play important roles in driving ovarian tumor progression and that these stromal cells represent attractive therapeutic targets. This review discusses the biological signiifcance of the cross-talk between ovarian cancer cells and three major types of stromal cells (endothelial cells, ifbroblasts and macrophages) and the development of new-generation therapies that target the ovarian tumor micro-environment.
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Tumor-stroma ratio is the ratio of tumor cells and stromal tissue. It can be evaluated through HE-stained sections. Usually a 50% cut-off value is taken. TSR is stratified as stroma rich(TSR < 50% )and stroma poor(TSR≥50% ). The different prognosis between the two groups can be assessed. Several previous studies show that TSR is an independent prognostic factor for colon carcinoma,breast cancer,esophageal squa-mous cell carcinoma,cervical carcinoma and non-small cell lung cancer;patients with stroma-rich tumor suffer worse prognosis. The cause might be that tumor cells could activate stroma cells while activated stroma cells could promote the growth,infiltration and metastasis of tumors. And tumor stroma should be recognized as an indispensible participant in progression and invasion of carcinoma.
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Chemotherapy, which includes preoperative chemotherapy (neoadjuvant chemotherapy) and postoperative chemotherapy, is one of the most important parts of systemic therapy in breast cancer. However, not every patient is sensitive to the chemotherapy. In recent years, it is reported that, apart from those of the tumor cells, the characteristics of stromal components could also affect the effectiveness of neoadjuvant chemotherapy, which include markers of immune cells, stromal fibroblasts, proteomic and genomic markers, etc. These researches bring new approaches to adjust the regimen and improve the effectiveness of neoadjuvant chemotherapy. This article aims at reviewing and summarizing the literature at these points. Copyright © 2012 by TUMOR.
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376 specimens consisting of 339 tumors and 37 alien tissues in the human host were studied with regards to the density of immunocellular infiltration (DI) at the tumor-stroma junction. The DI was read as 0,1,2,3,4, with 0 representing absence of the infiltrating immunocytes according to the authors proposed classificationThere was total disparity between the results of the control and that of the tumor group. Whereas the control group showed a 70.2% incidence, at DI 3 and 4 combined, the whole tumor group had only 18.1% and, therefore, a low immunocellular index (ICI) of 25.7% of the control (Group X). On the other hand, at DI 0 and 1, the tumor group had an incidence of 66.9%, while the control had only a 2.7% incidence at DI 1 and none at 0. It is striking that the high group incidences at DI 0 and 1 combined were sent in the invasive and metastic-embolic groups (73.7%) and 84.1%, respectively)The quantitative differences between the benign-preinvasive groups (A and B) and the invasive-metastatic groups (C and D) which have similar descending trends clearly point to their clearout behaviors, namely: the "host-dependent" and the "autonomous", respectively. The results of this study proved beyond doubt the immunosuppressive property of cancer. The experimental and clinical correlations with the above results were discussed. Mention was made also of the significance of the trophoblastic nature of cancer in relation to the authors findings. Fiscally, a hypothesis of "Cancer Rejection" was presented. and its various facets discussed. Preliminary clinical experimentation seems to support the hypothesis. These experiences may be the beginning of a relatively new challenge in oncotherapy. It can be said in closing that the various aspects of cancer immunology deserve an aggressive reappraisal, for this author is confident that in the not-too-distant future a much more simple, safe, and physiological method in the conquest of malignancy can become a living reality.(Summary)