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Background: Galectin-3 has an important role in metastasis, therefore, Galectin-3-focused therapies have attracted attention for various cancers. Aim: We aimed to reveal the relationship between the expression of Galectin-3 within the tumor/cancer-associated fibroblasts (CAF) and clinicopathological parameters in patients with invasive ductal carcinomas. Materials and Methods: Hematoxylin and eosin-stained slides of breast excision materials diagnosed between 2010 and 2016 were re-examined retrospectively. Accordingly, 118 cases (luminal group = 58, Human epidermal growth factor receptor 2 (HER2) group = 27, and triple-negative breast carcinoma group [TNBC] =33 cases) were included. Galectin-3 levels were evaluated with a calculated H-score in tumor and semiquantitatively in CAFs. Statistical Analysis: Data was analyzed with t-tests and Chi-square tests. Kaplan–Meier and Log-rank tests were used for survival analysis. Results: The presence of Galectin-3 expression in CAFs but not in the tumor was associated with the greater number of axillary metastatic nodes and advanced pN stage. The loss of Galectin-3 expression in CAFs was more frequent in TNBC. There was no significant relationship between the expression level of Galectin-3 and survival status. However, in most of the cases with distant metastasis or patients who died, Galectin-3 was negative in the tumor, whereas it was positive in CAFs. Conclusions: The expression of Galectin-3 in tumors and CAFs may have a role in metastasis to axillary lymph nodes and distant sites. In terms of molecular subtype, TNBCs show a relationship with Galectin-3 negativity in CAFs.
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Cancer-associated fibroblasts （CAF） are a key component of the tumor microenvironment, which can secrete a variety of cytokines, chemokines and growth factors, directly and indirectly support cancer cells, also alter the immune cellular environment by inhibiting the activity of immune effector cells and recruiting immunosuppressive cells, thereby allowing cancer cells to evade immune surveillance. CAF has been proven to be associated with the development, progression, and poor prognosis of solid tumors. However, the role of CAF in hematological malignancies is still unclear. This article reviews the research progress of CAF in hematological malignancies.
Subject(s)
Humans , Cancer-Associated Fibroblasts/pathology , Neoplasms/metabolism , Hematologic Neoplasms/metabolism , Tumor Microenvironment , Fibroblasts/pathologyABSTRACT
Cancer-associated fibroblasts (CAFs) is considered as a key factor for the severely limited efficacy in tumor radiotherapy. CAFs, as the primary stromal cells in the tumor microenvironment, can lead to tumor radiotherapy resistance by secreting a series of pro-tumor cytokines and nutrients, inhibiting anti-tumor immune response and remodeling extracellular matrix. Some progress has been made in the study of targeted CAFs sensitization radiotherapy, but the relevant study system is still imperfect. Therefore, a systematic exploration of the role of CAFs in tumor radiotherapy resistance and CAFs targeted therapy strategies can provide a basis for improving the current status of tumor radiotherapy resistance.
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Monoclonal antibody drugs that inhibit programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) have been widely used in esophageal cancer (EC) and yielded significant therapeutic responses. However, only a few patients obtain lasting clinical benefits due to primary or acquired drug resistance, and new treatment schemes are urgently needed. The tumor immune microenvironment is the main factor that affects patients' response to immunosuppressive agents. This article will discuss the role of immunosuppressive cells and non-cellular components in the immune process to provide ideas for the next research direction of EC.
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A large number of cancer-associated fibroblasts (CAFs) in tumor tissues create a favorable environment for the development of tumor. CAFs inhibit immune cells activation and viability by cytokine secretion, and CAFs prohibit drugs and immune cells infiltration by producing extracellular matrix to weaken cancer treatment efficacy. Regulating CAFs or overcoming CAFs barriers are new strategies for cancer therapy. Hence, designing nano-carriers for regulating CAFs to suppress tumor progression or promoting drug delivery to tumor site by overcoming CAFs barriers has attracted much attention. Therefore, this manuscript reviewed the recent progresses of nano-carriers for CAFs-targeting cancer therapies, in order to provide a reference for clinical cancer treatment.
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【Objective】 To investigate the effects of gallbladder cancer-associated fibroblasts (CAFs) on the migration of lymphatic endothelial cells (LECs) so as to elucidate the molecular mechanisms involved. 【Methods】 The CAFs and normal fibroblasts (NFs) were extracted by enzymatic digestion, and the supernatant (CM) of CAFs and NFs was collected. The levels of IL-6, IGFBP3 and other related cytokines were detected by semi-quantitative protein factor microarray and ELISA. The expressions of α-SMA (CAFs maker) and IGFBP3 in gallbladder cancer and para-cancer tissues were detected by immunohistochemistry, and the correlation of α-SMA and IGFBP3 expressions with clinicopathological characteristics were analyzed. LECs were cultured and divided into serum-free medium group (control group), CAF-CM co-culture group, NF-CM co-culture group, IGFBP3 group, and CAF-CM+IGFBP3 inhibitor (2-Deoxy-D-glucose, 2-DG) group according to different treatment. Transwell migration assays and wound healing assays were applied to analyze the migration ability of LECs under different treatment. The expressions of E-cadherin, N-cadherin and Vimentin were detected by Western blotting. 【Results】 Protein factor microarray and ELISA showed that the concentration of IGFBP3 in CAF-CM was significantly increased, and the expression of α-SMA was significantly related to lymph node metastasis, advanced TNM stage and expression of IGFBP3. IGFBP3 secreted from CAF-CM significantly promoted LECs migration, up-regulated the expression of N-cadherin and Vimentin, and down-regulated the expression of E-cadherin. Treatment with IGFBP3 inhibitor 2-DG could reverse the effect of CAF-CM on migration of LECs and related protein expressions. 【Conclusion】 Gallbladder CAFs promote the migration of LECs via releasing IGFBP3, which affects EMT transformation.
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AIM: To explore whether Agkistrodon Halys venom antitumor component-I (AHVAC-I) affects the migration of gastric cancer cells by human primary gastric cancer-associated fibroblast (GCAFs). METHODS: Tissue block culture and trypsin digestion were used to separate and culture human primary gastric cancer-associated fibroblasts (GCAFs); the GCAFs-CM
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Tumor cells along with a small proportion of cancer stem cells exist in a stromal microenvironment consisting of vasculature, cancer-associated fibroblasts, immune cells and extracellular components. Recent epidemiological and clinical studies strongly support that vitamin D supplementation is associated with reduced cancer risk and favorable prognosis. Experimental results suggest that vitamin D not only suppresses cancer cells, but also regulates tumor microenvironment to facilitate tumor repression. In this review, we have outlined the current knowledge on epidemiological studies and clinical trials of vitamin D. Notably, we summarized and discussed the anticancer action of vitamin D in cancer cells, cancer stem cells and stroma cells in tumor microenvironment, providing a better understanding of the role of vitamin D in cancer. We presently re-propose vitamin D to be a novel and economical anticancer agent.
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@#Cancer-associated fibroblasts (CAFs) are one of the major cellularcomponents in tumor microenvironment (TME), which play an important role in cancer progression. MicroRNAs (miRNAs) could participate in the process of CAFs, transformation and metabolism reprogramming, affect the stemness of CAFs, and regulate CAFs-mediated tumor cell proliferation, invasion and chemotherapy resistance; and studies have shown that miRNAs play an important role in CAFs formation and the regulation of CAFs on tumors. The miRNAs released by CAFs can be used as reference indicators for tumor diagnosis, prognosis and drug selection. Thus, exploring the role of miRNAs in the interaction between CAFs and tumor cells and underlining the mechanism, is of great significancefor understanding the occurrence and development of tumors, as well as providing novel strategy for cancer treatment. This review will summarize the role of miRNAs in the formation of CAFs and the regulation of CAFs on tumor cells.
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@# Objective: To investigate the effects of prostate cancer exosomes on the migration and invasion ability of stromal cells (WPMY-1), and to explore its mechanism. Methods: Exosomes in LNCaP-AI+F prostate cancer cell supernatant were isolated by ultracentrifugation and the typical structure of exosome was captured by electron microscope. The particle size distribution was analyzed by Zetaview, and Wb was used to identify the marker proteins and other proteins.After co-incubation of WPMY-1 cells and prostate cancer exosomes (40 µg/ml), laser confocal microscope was used to observe the uptake of PKH67-labeled exosomes by WPMY-1 cells; Transwell assay was used to detect the migration and invasion ability of WPMY-1 cells; qPCR was performed to detect the expression of three cancer-associated fibroblast (CAF)-related molecules (IL-8, PDGFB and MMP9) at mRNA level; and the phosphorylation of EGFR and ERK1/2 was analyzed by Wb. Results: Typical cup-shaped structure of exosomes was observed under electron microscope. The Zetaview results showed that the particle size distribution was concentrated at about 100 nm. The expression of exosome marker proteins CD63 andALIX further verified that the isolated particles were exosomes. Besides, EGFR, HER2 and SRC, which were related to the progression of prostate cancer, were also enriched in exosomes. After co-incubation, confocal microscope imaging showed a number of PKH67 labeled exosomes in recipient WPMY-1 cells. Transwell experiments showed that exosomes could significantly enhance the migration and invasion ability of WPMY-1 cells (all P<0.01). Compared with the control group, increased secretion of IL-8, PDGFB and MMP9 was observed after exosome treatment (40 µg/ml) (P<0.05 or P<0.01). Wb indicated that exosomes could promote the phosphorylation of EGFR and ERK1/2 of WPMY-1 cells (P<0.01). Conclusion: Prostate cancer cell exosomes could act on the stromal cell WPMY-1 to highly express multiple CAF-related molecules, promote the phosphorylation of EGFR and ERK1/2 and enhance the migration and invasion ability of WPMY-1 cells.
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Objective To investigate the effect of human bone marrow mesenchymal stem cells (BM-MSCs) stimulated by platelets in vitro on the metastasis of cancer cells.Methods The BM-MSCs were isolated and cultured in vitro and platelets from the peripheral blood of healthy persons were purified.The MSCs (control),platelets + MSCs,and platelets treated with culture media (CM) of SGC-7901 tumor cells + MSCs (T-platelets + MSCs) were cultured,respectively,and the MSCs and supernatants (MSCs-CM and SGC-7901-CM) were collected,respectively,after 24 hours.The expressions of markers of cancer-associated fibroblasts (CAF),such as α-SMA and Vimentin,were determined by Western-blotting.The immigration ability of BM-MSCs were analyzed by Transwell assay.The levels of P-selectin in platelets stimulated by MSCs-CM or SGC-7901-CM were detected with flow cytometry.The metastasis model of gastric cancer SGC-7901 cells was established in BALB/c nude mice by the injection of tail vein,and the tumor metastasis in vivo was observed.Results The expression levels of P-selectin in platelets stimulated by MSCs-CM ([21.37 ± 1.00] ％) or SGC-7901-CM ([31.4 ± 1.71] ％ were significantly higher than that in the control ([3.17 ± 0.40] ％,t =27.85 and 29.18,P ＜ 0.01).The expression levels of α-SMA and Vimentin in platelets + MSCs group (0.79 ± 0.08 and 0.88 ± 0.01) and T-platelets + MSCs group (0.90 ±0.06 and 0.96 ±0.04) were significantly higher than that in the control (0.64 ±0.02 and 0.75 ±0.05,t =2.96 and 6.45 forα-SMA,t =4.73 and 5.73 for Vimentin,P ＜0.01).The amounts of immigration cells in platelets + MSCs group (340.3 ±27.7) and T-platelets ± MSCs group (424.3 ± 17.6) were significantly higher than that in the control (220.7 ± 19.4,t =6.14 and 13.48,P ＜ 0.01).The in vivo experimental results showed that the metastatic foci in platelets ± MSCs group (4 ± 2) and T-platelets ± MSCs group (21 ± 4) were significantly higher than that in the control (0.33 ± 0.06,t =3.051 and 8.857,P ＜ 0.01).Conclusion Platelets promote the immigration and the enhanced tumor metastasis in vivo of BM-MSCs.
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The interactions between the tumor microenvironment and tumor cells determine the behavior of the primary tumors. Whether cancer-associated fibroblasts (CAF) have a tumor progressive or a protective role likely depends on the type of tumor cells and the CAF subpopulation. In the present study, we analyzed the prognostic significance of CAF subpopulations in colorectal cancer (CRC). CAF phenotypes were analyzed in 302 CRC patients by using antibodies against podoplanin (PDPN), alpha-smooth muscle actin (alpha-SMA), and S100A4. The relationship between the CAF phenotypes and 11 clinicopathological parameters were evaluated and their prognostic significance was analyzed from the disease-free and overall survival times. We observed that at the tumor invasive front, PDPN CAFs were present in 40% of the cases, and S100A4 or alpha-SMA CAFs were detected in all the cases. PDPN/S100A4 and alpha-SMA/S100A4 dual-stained CAFs were observed in 10% and 40% of the cases, respectively. The PDPN+ CAFs were associated with 6 favorable clinicopathological parameters and prolonged disease-free survival time. The PDPN-/alpha-SMA(high) CAFs were associated with 6 aggressive clinicopathological parameters and tended to exhibit shorter disease-free survival time. On the other hand, the PDPN-/S100A4(high) CAFs were associated with 2 tumor progression parameters, but not with disease prognosis. The PDPN+ CAF phenotype is distinct from the alpha-SMA or S100A4 CAFs in that it is associated with less aggressive tumors and a favorable prognosis, whereas the PDPN-/alpha-SMA(high) or PDPN-/S100A4(high) CAFs are associated with tumor progression in CRC. These findings suggest that CAFs can be a useful prognostic biomarker or potential targets of anti-cancer therapy in CRC.