The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells. 

/pdf/the-functional-role-of-extracellular-matrix-proteins-in-2zdlu8a6.pdf

The Functional Role of Extracellular Matrix Proteins in Cancer

Background: Collagen type VI alpha 1 (COL6A1) has been found to be dysregulated in several human malignancies. However, the role of COL6A1 in osteosarcoma (OS) progression remains largely unclear. Here, we aimed to explore the clinical significance and biological involvement of COL6A1 in the OS cell migration and invasion. Material and Methods: We used immunohistochemistry, qRT-PCR and western blot to detect the expression of COL6A1 in 181 OS patient samples. Chromatin immunoprecipitation (ChIP) and PCR were carried out to verify the regulatory interaction of p300, c-Jun and COL6A1 promoter. The invasion and migration function of COL6A1 in OS was detected in vitro and in vivo. RNA sequence was performed to detect the downstream pathway of COL6A1, and then co-immunoprecipitation (co-IP), ubiquitination assays and rescue experiments were performed to determine the regulatory effect of COL6A1 and signal transducers and activators of transcription (STAT1). Exosomes derived from OS cell lines were assessed for the ability to promote cancer progression by co-cultured assay and exosomes tracing. Results: COL6A1 was commonly upregulated in OS tissues, especially in lung metastasis tissues, which was associated with a poor prognosis. c-Jun bound p300 increased the enrichment of H3K27ac at the promoter region of the COL6A1 gene, which resulted in the upregulation of COL6A1 in OS. Overexpression of COL6A1 promoted OS cell migration and invasion via interacting with SOCS5 to suppress STAT1 expression and activation in an ubiquitination and proteasomal degradation manner. Most interestingly, we found that exosomal COL6A1 derived from OS cells convert normal fibroblasts to cancer-associated fibroblasts (CAFs) by secreting pro-inflammatory cytokines, including IL-6 and IL-8. The activated CAFs could promote OS cell invasion and migration by mediating TGF-β/COL6A1 signaling pathway. Conclusion: Our data demonstrated that upregulation of COL6A1 activated by H3K27 acetylation promoted the cell migration and invasion by suppressing STAT1 pathway in OS cells. Moreover, COL6A1 can be packaged into OS cell-derived exosomes and activate CAFs to promote OS metastasis.

H3K27 acetylation activated-COL6A1 promotes osteosarcoma lung metastasis by repressing STAT1 and activating pulmonary cancer-associated fibroblasts.

Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of the key, complex and multiple roles of the ECM in cancer and of the CAF diversity, has revolutionized the field and raised innovative but challenging questions. Here, we rapidly present CAF heterogeneity in link with their specific ECM remodeling features observed in cancer, before developing each of the impacts of such ECM modifications on tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc.), and on patient prognosis. Finally, based on preclinical studies and recent results obtained from clinical trials, we highlight key mechanisms or proteins that are, or may be, used as potential therapeutic or diagnostic targets, and we report and discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies.

https://www.mdpi.com/2072-6694/13/14/3466/pdf

Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?

Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer-associated fibroblasts (CAFs). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has dual function in CAFs - it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging.

Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness

Stromal heterogeneity of tumor microenvironment (TME) plays a crucial role in malignancy and therapeutic resistance. Cancer-associated fibroblasts (CAFs) are one of the major players in tumor stroma. The heterogeneous sources of origin and subsequent impacts of crosstalk with breast cancer cells flaunt serious challenges before current therapies to cure triple-negative breast cancer (TNBC) and other cancers. The positive and reciprocal feedback of CAFs to induce cancer cells dictates their mutual synergy in establishing malignancy. Their substantial role in creating a tumor-promoting niche has reduced the efficacy of several anti-cancer treatments, including radiation, chemotherapy, immunotherapy, and endocrine therapy. Over the years, there has been an emphasis on understanding CAF-induced therapeutic resistance in order to enhance cancer therapy results. CAFs, in the majority of cases, employ crosstalk, stromal management, and other strategies to generate resilience in surrounding tumor cells. This emphasizes the significance of developing novel strategies that target particular tumor-promoting CAF subpopulations, which will improve treatment sensitivity and impede tumor growth. In this review, we discuss the current understanding of the origin and heterogeneity of CAFs, their role in tumor progression, and altering the tumor response to therapeutic agents in breast cancer. In addition, we also discuss the potential and possible approaches for CAF-mediated therapies.

Cancer-associated fibroblasts: The chief architect in the tumor microenvironment

Pancreatic cancer is one of the most aggressive cancers worldwide with a high mortality rate. Prognosis remains poor even in this era of advanced medicine mainly due to early metastasis and invasion. The present study aimed to explore and validate predictors of distant metastasis and prognosis in pancreatic cancer. In our preliminary experiment, we established a novel metastatic pancreatic cancer cell line BxPC-M8 from parent BxPC-3 cells. Via whole genome sequencing, RT-qPCR, western blotting, migration and invasion assays, we initially found that BxPC-M8 shared similar biological characteristics to BxPC-3, but only differed in enhanced metastatic and invasive capabilities with a significant increase in collagen type VI α1 chain (COL6A1) expression. Knockdown of COL6A1 via small interfering RNA led to a significant decrease in migration and invasion of BxPC-M8 cells, suggesting suppressed epithelial-mesenchymal transition. Furthermore, a significant increase in COL6A1 expression was observed in cancerous tissue compared with paracancerous tissue (40.7 vs 3.7, P=0.001). Additionally, its expression was observed to be significantly associated with distant metastasis and vascular invasion at the time of surgery. Multivariate analysis revealed that COL6A1 expression (hazard ratio 1.90, 95% confidence interval 1.04-3.47, P=0.037) is an independent predictor of overall survival (OS). The median OS observed for COL6A1+ and COL6A1− patients was found to be 8±4 and 14±7 months (P=0.021), respectively. Of note, we identified that COL6A1 expression in tissue samples was associated with significantly reduced OS (P=0.001), demonstrating that COL6A1 may serve an important role in the metastatic process and could be considered as a predictor of poor outcomes in patients with pancreatic cancer. In addition, our findings suggest that COL6A1 could be an indicator of distant metastasis and a valid prognostic predictor in such patients; however, further investigation is required.

/pdf/col6a1-promotes-metastasis-and-predicts-poor-prognosis-in-28jgzln0sx.pdf

COL6A1 promotes metastasis and predicts poor prognosis in patients with pancreatic cancer.

For limited clinical benefits and acquired resistance by sorafenib, new therapeutic strategies and molecular targets for the treatment of advanced hepatocellular carcinoma (HCC) are urgently needed. This study aimed to evaluate the potential antitumor effects of the second-generation proteasome inhibitor delanzomib on HCC. The results demonstrated that delanzomib displayed excellent antitumor activity on HCC cells with sensitivity or resistance to sorafenib in a time- and dose-response manner, by inducing G2/M cell cycle arrest and apoptosis in vitro. Cell cycle arrest was associated with the activation of p21/Cdc2/cyclin B1 pathway, and cell apoptosis was confirmed by PARP and caspase-3 cleavage. In addition, delanzomib induced endoplasmic reticulum stress (ERS) in HCC cells by activating the PERK and ERS-associated proteins including p-eIF2α, ATF4 and CHOP. Selective inhibition of eIF2α dephosphorylation by salubrinal could significantly reduce delanzomib-induced apoptosis in HCC cells. In vivo, delanzomib could also exhibit effective antitumor properties on patient-derived xenograft mouse model of HCC with relative low drug-associated cytotoxicity. Compared to control group, 3 and 10 mg/kg of delanzomib significantly reduced the tumor volume by 33.1% and 87.2% respectively after 3 weeks treatment, with no significant change on the body weight and the level of serum biochemical indexes including ALT, AST and BUN. In conclusion, delanzomib could exhibit good pre-clinical antitumor effects against HCC cells by inducing ERS and activating the PERK/eIF2α/ATF4/CHOP pathway, as potential drug candidate on treatment of advanced HCC patients.

Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK/eIF2α/ATF4/CHOP pathway.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Jun Li

Author Tools

Chat about Author

Papers

COL6A1 promotes metastasis and predicts poor prognosis in patients with pancreatic cancer.

Endoplasmic reticulum stress triggers delanzomib-induced apoptosis in HCC cells through the PERK/eIF2α/ATF4/CHOP pathway.