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(A) Endoscopic view of scirrhous type gastric cancer (SGC); (B) Image of resected specimens of total gastrectomy. Tumors did not have marked ulceration or raised margins, the gastric wall was thickened, showing typical macroscopic view of SGC. (C, D) Microscopic images from the specimen shown in (B). Cancer cells are invading into the stroma containing fibroblasts and extracellular matrix.
Source publication
Gastric cancer (GC) is the third leading cause among all cancer deaths globally. Although the treatment outcome of GC has improved, the survival of patients with GC at stages III and IV remains unsatisfactory. Among several types of GC, scirrhous type GC (SGC) shows highly aggressive growth and invasive activity, leading to frequent peritoneal meta...
Citations
... During peritoneal metastasis of DGC, CAFs within the peritoneum support the colonization and growth of metastasized cancer cells [24]. We recently reported that DGC cells attach to the mesothelium of the peritoneal membrane as multicellular clusters [25] (Figure 2). ...
... DGC is caused by the loss of E-cadherin function, as evidenced by the fact that hereditary DGC is caused by germline mutations in E-cadherin. Consequently, solitary poorly differentiated cancer cells exist within the massive fibrous stroma of DGC tissues [24]. Therefore, such cancer cells are assumed to use an alternative approach to contact CAFs, independent of E-cadherin. ...
Simple Summary
Invasion of cancer into surrounding tissues is crucial for it to spread to other parts of the body, a process known as metastasis. The characteristics of cancer cells within tumors are significantly influenced by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the primary cellular component of the TME and play a pivotal role in cancer progression, including growth, invasion, metastasis, therapy resistance, and immune suppression. Numerous factors mediating interactions between CAFs and cancer cells have been identified, such as growth factors, cytokines, and extracellular vesicles. Recent studies have highlighted the importance of direct contact between CAFs and cancer cells in facilitating cancer invasion and metastasis to distant organs. This review summarizes recent findings on the molecular and cellular mechanisms underlying this direct heterocellular adhesion, providing insights into how CAFs drive cancer invasion and metastasis.
Abstract
Cancer invasion is a requisite for the most malignant progression of cancer, that is, metastasis. The mechanisms of cancer invasion were originally studied using in vitro cell culture systems, in which cancer cells were cultured using artificial extracellular matrices (ECMs). However, conventional culture systems do not precisely recapitulate in vivo cancer invasion because the phenotypes of cancer cells in tumor tissues are strongly affected by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the TME and accelerate cancer progression through invasion, metastasis, therapy resistance, and immune suppression. Thus, the reciprocal interactions between CAFs and cancer cells have been extensively studied, leading to the identification of factors that mediate cellular interactions, such as growth factors, cytokines, and extracellular vesicles. In addition, the importance of direct heterocellular adhesion between cancer cells and CAFs in cancer progression has recently been elucidated. In particular, CAFs are directly associated with cancer cells, allowing them to invade the ECM and metastasize to distant organs. In this review, we summarize the recent progress in understanding the molecular and cellular mechanisms of the direct heterocellular interaction in CAF-led cancer invasion and metastasis, with an emphasis on gastric cancer.
... This report focused on the prognostic significance of CTGF in GC. GC has been histologically classified into intestinal and diffuse types by Lauren (10), and diffuse-type GC usually has a lot of stromal components in the tumor tissue (11)(12)(13). Generally, the interaction between cancer and stromal cells is crucial for the progression of diffuse-type GC (14,15). However, Chen et al (9) did not pay attention to the difference in histological type. ...
Connective tissue growth factor (CTGF) is a target gene of the Hippo signaling pathway. Its differential role in the histological types of gastric cancer (GC) remains unknown; therefore, the present study aimed to confirm the clinical significance of CTGF expression in cancer and stromal cells in patients with GC depending on the histological type. The present study enrolled 589 patients with GC. Immunohistochemistry was used to analyze CTGF expression in cancer and stromal cells. CTGF mRNA expression data and the corresponding clinical information of GC samples were collected from The Cancer Genome Atlas (TCGA) database. Subsequently, the associations between CTGF expression and several clinicopathological factors were investigated. In the present study, CTGF expression was mainly observed in the cytoplasm of cancer and stromal cells. CTGF expression in stromal cells was significantly associated with CTGF expression in cancer cells (P<0.001). CTGF positivity in stromal cells was also significantly associated with intestinal type, non-scirrhous type, tumor depth (T1-2), lymph node metastasis (negative), lymphatic invasion (negative) and tumor size (<5 cm). Low CTGF expression in stromal cells was independently associated with worse overall survival (OS). Furthermore, the OS of patients with low CTGF expression in stromal cells, especially in patients with diffuse-type GC, was significantly worse than patients with high CTGF expression (P=0.022). This trend was similar to that revealed by TCGA data analysis. In conclusion, low CTGF expression was associated with a significantly worse OS in patients with diffuse-type GC. These data indicated that CTGF, and its control by the Hippo pathway, may be considered potential treatment targets in diffuse-type GC.
... LP originates from the fundic gland cells and infiltrates the entire stomach with a desmoplastic growth pattern, unlike the development of a solid tumor. Tumor cells are dispersed within the thickened fibrous tissue, extending into the submucosal and serous layer [5,7,[9][10][11]. In 91.1% of cases, LP presents as a poorly differentiated adenocarcinoma, and in 77.7% of cases, it is often histologically linked with signet ring cells [8]. ...
... However, these mutations in scirrhous cancer result in a distinct invasive and metastatic pattern, significantly decreasing any chance of survival. Determining is the role of stromal mutations and the influence of stromal cells to the cancerous ones [2,7,10,14]. Cancerous cells in LP often develop in hypoxic conditions, activating HIF-1a (Hypoxia Induced Factor), which, in turn, induces the production of ANGPTL4 [15]. ...
... The methylation of the CDH1 gene down-regulates the expression of E-cadherin [3]. E-cadherin and Desmoglein-2 mutations also play a crucial role in the invasive pattern of LP [10]. The down-regulation of E-cadherin expression is additionally derived from the low expression of miRNA-200c, which results in the over-expression of ZEB1 and, subsequently, a depletion of E-cadherin [2]. ...
Linitis Plastica (LP) is a rare and aggressive tumor with a distinctive development pattern, leading to the infiltration of the gastric wall, the thickening of the gastric folds and a “leather bottle appearance”. LP is an extremely heterogeneous tumor caused by mutations in oncogenic and tumor suppressive genes, as well as molecular pathways, along with mutations in stromal cells and proteins related to tight junctions. Elucidating the molecular background of tumorigenesis and clarifying the correlation between cancerous cells and stromal cells are crucial steps toward discovering novel diagnostic methods, biomarkers and therapeutic targets/agents. Surgery plays a pivotal role in LP management, serving both as a palliative and curative procedure. In this comprehensive review, we aim to present all recent data on the molecular background of LP and the novel approaches to its management.
... It can also be observed that all the collagen proteins are strongly linked to the SERPINH1 gene ( Figure 2D, Figure 4D), which according to the STRING database, is a serine protease inhibitor and plays a role in collagen processing by acting as a chaperone. Lastly, we also looked at the expression of various ligands secreted by stromal cells, particularly the CAF component of stroma, which has been listed in multiple secretome studies and reviews [22][23][24][25][26][27][28] . Here we also focused on reporting only those factors which were differentially expressed (FDR < 0.05) in all three comparisons. ...
Objective
Alpha smooth muscle actin (alpha-SMA) expression in stroma is linked to the presence of cancer-associated fibroblasts and is known to correlate with worse outcomes in various tumors. In this study, using a digital spatial profiling approach, we characterized the gene expression profiles of the tumor and alpha-SMA positive stromal cell compartments in pancreatic neuroendocrine tumor (PanNET) tissues.
Methods
The profiling was performed in tissues from eight retrospective cases (Three Grade 1, four Grade 2, and one Grade 3) where the segmentation was done based on tissue morphology and synaptophysin (tumor), alpha-SMA (stroma) marker expression.
Results
The stromal cell-associated genes were mainly involved in pathways of extracellular matrix modification, while in tumor cells, the gene expression profiles were primarily associated with the pathways involved in cell proliferation. The comparison of gene expression profiles across all three PanNET grades revealed that heterogeneity is not only present within the tumor but also in the alpha-SMA positive stromal cells. Furthermore, the comparison of tumor cells adjacent versus non-adjacent to α-SMA positive stromal cells revealed an upregulation of MMP9 in G3 tumor analysis.
Conclusions
Overall, this study provides an in-depth characterization of gene expression profiles in both stroma and tumor cells of PanNETs and outlies potential crosstalk mechanisms.
... During peritoneal metastasis of DGC, CAFs within the peritoneum support the colonization and growth of metastasized cancer cells [24]. We recently reported that DGC cells attach to the mesothelium of the peritoneal membrane as multicellular clusters [25] (Figure 2). ...
... DGC is caused by the loss of E-cadherin function, as evidenced by the fact that hereditary DGC is caused by germline mutations in E-cadherin. Consequently, solitary poorly differentiated cancer cells exist within the massive fibrous stroma of DGC tissues [24]. Therefore, such cancer cells are assumed to use an alternative approach to contact CAFs, independent of E-cadherin. ...
Simple Summary: Invasion of cancer into surrounding tissues is crucial for it to spread to other parts of the body, a process known as metastasis. The characteristics of cancer cells within tumors are significantly influenced by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the primary cellular component of the TME and play a pivotal role in cancer progression, including growth, invasion, metastasis, therapy resistance, and immune suppression. Numerous factors mediating interactions between CAFs and cancer cells have been identified, such as growth factors, cytokines, and extracellular vesicles. Recent studies have highlighted the importance of direct contact between CAFs and cancer cells in facilitating cancer invasion and metastasis to distant organs. This review summarizes recent findings on the molecular and cellular mechanisms underlying this direct heterocellular adhesion, providing insights into how CAFs drive cancer invasion and metastasis. Abstract: Cancer invasion is a requisite for the most malignant progression of cancer, that is, metasta-sis. The mechanisms of cancer invasion were originally studied using in vitro cell culture systems, in which cancer cells were cultured using artificial extracellular matrices (ECMs). However, conventional culture systems do not precisely recapitulate in vivo cancer invasion because the phenotypes of cancer cells in tumor tissues are strongly affected by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the TME and accelerate cancer progression through invasion, metastasis, therapy resistance, and immune suppression. Thus, the reciprocal interactions between CAFs and cancer cells have been extensively studied, leading to the identification of factors that mediate cellular interactions, such as growth factors, cytokines, and extracellular vesicles. In addition, the importance of direct heterocellular adhesion between cancer cells and CAFs in cancer progression has recently been elucidated. In particular, CAFs are directly associated with cancer cells, allowing them to invade the ECM and metastasize to distant organs. In this review, we summarize the recent progress in understanding the molecular and cellular mechanisms of the direct heterocellular interaction in CAF-led cancer invasion and metastasis, with an emphasis on gastric cancer.
... CAFs are one of the major cell types of tumor stroma and communicate with tumor cells and immune cells, thereby promoting or suppressing cancer progression (Kalluri and Zeisberg, 2006;Xouri and Christian, 2010;Alguacil-Núñez et al., 2018;Kobayashi et al., 2019;Miki et al., 2020;Miyai et al., 2020;Biffi and Tuveson, 2021). Very much similar to the "mesenchymal state", CAFs are also an undefinable cell state because they are heterogeneous in marker expression, function and inter-and intra-tumoral phenotypes (Kobayashi et al., 2019;Biffi and Tuveson, 2021). ...
Characterization of cancer cells and neural stem cells indicates that tumorigenicity and pluripotency are coupled cell properties determined by neural stemness, and tumorigenesis represents a process of progressive loss of original cell identity and gain of neural stemness. This reminds of a most fundamental process required for the development of the nervous system and body axis during embryogenesis, i.e., embryonic neural induction. Neural induction is that, in response to extracellular signals that are secreted by the Spemann-Mangold organizer in amphibians or the node in mammals and inhibit epidermal fate in ectoderm, the ectodermal cells lose their epidermal fate and assume the neural default fate and consequently, turn into neuroectodermal cells. They further differentiate into the nervous system and also some non-neural cells via interaction with adjacent tissues. Failure in neural induction leads to failure of embryogenesis, and ectopic neural induction due to ectopic organizer or node activity or activation of embryonic neural genes causes a formation of secondary body axis or a conjoined twin. During tumorigenesis, cells progressively lose their original cell identity and gain of neural stemness, and consequently, gain of tumorigenicity and pluripotency, due to various intra-/extracellular insults in cells of a postnatal animal. Tumorigenic cells can be induced to differentiation into normal cells and integrate into normal embryonic development within an embryo. However, they form tumors and cannot integrate into animal tissues/organs in a postnatal animal because of lack of embryonic inducing signals. Combination of studies of developmental and cancer biology indicates that neural induction drives embryogenesis in gastrulating embryos but a similar process drives tumorigenesis in a postnatal animal. Tumorigenicity is by nature the manifestation of aberrant occurrence of pluripotent state in a postnatal animal. Pluripotency and tumorigenicity are both but different manifestations of neural stemness in pre- and postnatal stages of animal life, respectively. Based on these findings, I discuss about some confusion in cancer research, propose to distinguish the causality and associations and discriminate causal and supporting factors involved in tumorigenesis, and suggest revisiting the focus of cancer research.
... Abnormal collagen fiber deposition was found in colorectal cancer grown in macrophage-deficient mice [73]. Precisely, TAMs can regulate collagen production by stimulating CAFs [73,74]. In pancreatic cancer, TAMderived C-X-C motif chemokine ligand 3 (CXCL3) targets CAFs' C-X-C motif chemokine receptor 2 (CCR2) to mediate CAF-myofibroblasts (myCAF) transition, subsequent type III collagen generation and tumor metastasis [75]. ...
The malignant tumor is a multi-etiological, systemic and complex disease characterized by uncontrolled cell proliferation and distant metastasis. Anticancer treatments including adjuvant therapies and targeted therapies are effective in eliminating cancer cells but in a limited number of patients. Increasing evidence suggests that the extracellular matrix (ECM) plays an important role in tumor development through changes in macromolecule components, degradation enzymes and stiffness. These variations are under the control of cellular components in tumor tissue via the aberrant activation of signaling pathways, the interaction of the ECM components to multiple surface receptors, and mechanical impact. Additionally, the ECM shaped by cancer regulates immune cells which results in an immune suppressive microenvironment and hinders the efficacy of immunotherapies. Thus, the ECM acts as a barrier to protect cancer from treatments and supports tumor progression. Nevertheless, the profound regulatory network of the ECM remodeling hampers the design of individualized antitumor treatment. Here, we elaborate on the composition of the malignant ECM, and discuss the specific mechanisms of the ECM remodeling. Precisely, we highlight the impact of the ECM remodeling on tumor development, including proliferation, anoikis, metastasis, angiogenesis, lymphangiogenesis, and immune escape. Finally, we emphasize ECM "normalization" as a potential strategy for anti-malignant treatment.
... (Fig. 7). Exosomal miR-522 secreted by CAFs targets ALOX15 to activate the USP7/hnRNPA1 pathway, blocking lipid-ROS accumulation and inhibiting the ferroptosis of gastric cancer cells [258,283]. Exosomal lncRNA SNHG3 secreted by CAFs serves as a molecular sponge for miR-330-5p in breast cancer cells. MiR-330-5p further targets PKM to inhibit OXPHOS and promote glycolysis, favoring breast cancer cells proliferation [259]. ...
Metabolic reprogramming is one of the hallmarks of cancer. As nutrients are scarce in the tumor microenvironment (TME), tumor cells adopt multiple metabolic adaptations to meet their growth requirements. Metabolic reprogramming is not only present in tumor cells, but exosomal cargos mediates intercellular communication between tumor cells and non-tumor cells in the TME, inducing metabolic remodeling to create an outpost of microvascular enrichment and immune escape. Here, we highlight the composition and characteristics of TME, meanwhile summarize the components of exosomal cargos and their corresponding sorting mode. Functionally, these exosomal cargos-mediated metabolic reprogramming improves the "soil" for tumor growth and metastasis. Moreover, we discuss the abnormal tumor metabolism targeted by exosomal cargos and its potential antitumor therapy. In conclusion, this review updates the current role of exosomal cargos in TME metabolic reprogramming and enriches the future application scenarios of exosomes.
... CAFs are one of the major cell types of tumor stroma and communicate with tumor cells and immune cells, thereby promoting or suppressing cancer progression (Alguacil-Núñez et al, 2018;Biffi and Tuveson, 2021;Kalluri and Zeisberg, 2006;Kobayashi et al., 2019;Miki et al., 2020;Miyai et al., 2020;Xouri and Christian, 2010). Very much similar to the "mesenchymal state", CAFs are also an undefinable cell state because they are heterogeneous in marker expression, function and inter-and intra-tumoral phenotypes (Biffi and Tuveson, 2021;Kobayashi et al., 2019). ...
Characterization of cancer cells and neural stem cells indicates that tumorigenicity and pluripotency are coupled cell properties determined by neural stemness, and tumorigenesis represents a process of progressive loss of original cell identity and gain of neural stemness. This reminds of a most fundamental process required for the development of the nervous system and body axis during embryogenesis, i.e., embryonic neural induction. Neural induction is that, in response to extracellular signals that are secreted by the Spemann-Mangold organizer in amphibians or the node in mammals and inhibit epidermal fate in ectoderm, the ectodermal cells lose their epidermal fate and assume the neural default fate and consequently, turn into neuroectodermal cells. They further differentiate into the nervous system and also some non-neural cells via interaction with adjacent tissues. Failure in neural induction leads to failure of embryogenesis, and ectopic neural induction due to ectopic organizer or node activity or activation of embryonic neural genes causes a formation of secondary body axis or a conjoined twin. During tumorigenesis, cells progressively lose their original cell identity and gain of neural stemness, and consequently, gain of tumorigenicity and pluripotency, due to various intra-/extracellular insults in cells of a postnatal animal. Tumorigenic cells can be induced to differentiation into normal cells and integrate into normal embryonic development within an embryo. However, they form tumors and cannot integrate into animal tissues/organs in a postnatal animal because of lack of embryonic inducing signals. Combination of studies of developmental and cancer biology indicates that neural induction drives embryogenesis in gastrulating embryos but a similar process drives tumorigenesis in a postnatal animal. Tumorigenicity is the manifestation of aberrant occurrence of pluripotent state in a postnatal animal. Pluripotency and tumorigenicity are both but different manifestations of neural stemness in pre- and postnatal stage, respectively, of animal life. The unique property of neural stemness is derived from the evolutionary advantage of neural genes and the neural-biased state of the last common unicellular ancestors of metazoan. Based on these findings, I discuss about some confusion in cancer research, propose to distinguish the causality and associations and discriminate causal and supporting factors involved in tumorigenesis, and suggest revisiting the focus of cancer research.
... In particular, there is a highly aggressive subtype of GC with a very poor prognosis -scirrhous gastric cancer (SGC), which is characterized by rapid infiltration and proliferation of tumor cells with extensive stromal fibrosis [34]. In this fibrotic TME of SGC, researchers explored the biological behavior by constructing SGC cell lines and mouse models [35], gradually depicting the crosstalk between tumor cells and CAFs [34,36]. ...
As the dominant component of the tumor microenvironment, cancer-associated fibroblasts (CAFs), play a vital role in tumor progression. An increasing number of studies have confirmed that CAFs are involved in almost every aspect of tumors including tumorigenesis, metabolism, invasion, metastasis and drug resistance, and CAFs provide an attractive therapeutic target. This study aimed to explore the feature genes of CAFs for potential therapeutic targets and reliable prediction of prognosis in patients with gastric cancer (GC). Bioinformatic analysis was utilized to identify the feature genes of CAFs in GC by performing an integrated analysis of single-cell and transcriptome RNA sequencing using R software. Based on these feature genes, a CAF-related gene signature was constructed for prognostic prediction by LASSO. Simultaneously, survival analysis and nomogram were performed to validate the prognostic predictive value of this gene signature, and qRT–PCR and immunohistochemical staining verified the expression of the feature genes of CAFs. In addition, small molecular drugs for gene therapy of CAF-related gene signatures in GC patients were identified using the connectivity map (CMAP) database. A combination of nine CAF-related genes was constructed to characterize the prognosis of GC, and the prognostic potential and differential expression of the gene signature were initially validated. Additionally, three small molecular drugs were deduced to have anticancer properties on GC progression. By integrating single-cell and bulk RNA sequencing analyses, a novel gene signature of CAFs was constructed. The results provide a positive impact on future research and clinical studies involving CAFs for GC.
