Implications of CXCR4/CXCL12 Interaction for Cancer Stem Cell Maintenance and Cancer Progression

Peitzsch, Claudia; Cojoc, Monica; Kurth, Ina; Dubrovska, Anna

doi:10.1007/978-3-319-21030-8_4

Cited by 4 publications

(5 citation statements)

References 258 publications

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“…This suggests that myCAFs may have a different biological role in the tumor microenvironment. In addition to their very high levels of CXCR4 expression, CXCR4+ iCAFs express very high levels of its ligand, CXCL12 ( Figure S5D ) (Liekens et al, 2010; Peitzsch et al, 2015; Eckert et al, 2018). Also, while apCAFs have high expression of NFE2L2, which is involved in oxidative damage repair, myCAFs have high expression of HIF1A, which regulates tolerance to hypoxic environments ( Figure S5E ).…”

Section: Resultsmentioning

confidence: 99%

Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Zhou

Jayasinghe

Herndon

et al. 2021

Preprint

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SUMMARYPancreatic Ductal Adenocarcinoma (PDAC) is a lethal disease with limited treatment options and poor survival. We studied 73 samples from 21 patients (7 treatment-naïve and 14 treated with neoadjuvant regimens), analyzing distinct spatial units and performing bulk proteogenomics, single cell sequencing, and cellular imaging. Spatial drivers, including mutant KRAS, SMAD4, and GNAQ, were associated with differential phosphosignaling and metabolic responses compared to wild type. Single cell subtyping discovered 12 of 21 tumors with mixed basal and classical features. Trefoil factor family members were upregulated in classical populations, while the basal populations showed enhanced expression of mesenchymal genes, including VIM and IGTB1. Acinar-ductal metaplasia (ADM) populations, present in 95% of patients, with 46% reduction of driver mutation fractions compared to tumor populations, exhibited suppressive and oncogenic features linked to morphologic states. We identified coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin receptor expression in tumor cells. Higher expression of angiogenic and stress response genes in dendritic cells compared to tumor cells suggests they have a pro-tumorigenic role in remodeling the microenvironment. Treated samples contain a three-fold enrichment of inflammatory CAFs when compared to untreated samples, while other CAF subtypes remain similar. A subset of tumor and/or ADM-specific biomarkers showed differential expression between treatment groups, and several known drug targets displayed potential cross-cell type reactivities. This resolution that spatially defined single cell omics provides reveals the diversity of tumor and microenvironment populations in PDAC. Such understanding may lead to more optimal treatment regimens for patients with this devastating disease.HIGHLIGHTSAcinar-ductal metaplasia (ADM) cells represent a genetic and morphologic transition state between acinar and tumor cells.Inflammatory cancer associated fibroblasts (iCAFs) are a major component of the PDAC TME and are significantly higher in treated samplesReceptor-ligand analysis reveals tumor cell-TME interactions through NECTIN4-TIGITTumor and ADM cell proteogenomics differ between treated and untreated samples, with unique and shared potential drug targets

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Section: Resultsmentioning

confidence: 99%

Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Zhou

Jayasinghe

Herndon

et al. 2021

Preprint

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“…75 80 Activation of CXCR4 stimulates key functions of CSCs, including self-renewal, local invasion, and dissemination to secondary organs and tissues. [85][86][87] In pancreatic cancer, CXCR4 demarks a highly metastatic subset of CSCs. 88 Key functions of CXCR4 in CSCs suggest that inhibiting CXCR4 signaling may be an effective strategy to reduce or eliminate CSCs in multiple malignancies.…”

Section: Cxcr4 Signaling and Cancer Stem Cellsmentioning

confidence: 99%

“…Up‐regulation of CXCR4 through mechanisms including PI3K/AKT/mTOR signaling and transcription activated by ΔNP63α, the predominant isoform of TP63 in epithelium, increases abundance and phenotypes of CSCs 80 . Activation of CXCR4 stimulates key functions of CSCs, including self‐renewal, local invasion, and dissemination to secondary organs and tissues 85–87 . In pancreatic cancer, CXCR4 demarks a highly metastatic subset of CSCs 88 .…”

Section: Cxcr4 Signaling and Cancer Stem Cellsmentioning

confidence: 99%

At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer

Luker

Yang

Richmond

et al. 2020

Journal of Leukocyte Biology

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Signaling through chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) regulates essential processes in normal physiology, including embryogenesis, tissue repair, angiogenesis, and trafficking of immune cells. Tumors co-opt many of these fundamental processes to directly stimulate proliferation, invasion, and metastasis of cancer cells. CXCR4 signaling contributes to critical functions of stromal cells in cancer, including angiogenesis and multiple cell types in the tumor immune environment. Studies in animal models of several different types of cancers consistently demonstrate essential functions of CXCR4 in tumor initiation, local invasion, and metastasis to lymph nodes and distant organs. Data from animal models support clinical observations showing that integrated effects of CXCR4 on cancer and stromal cells correlate with metastasis and overall poor prognosis in >20 different human malignancies. Small molecules, Abs, and peptidic agents have shown anticancer efficacy in animal models, sparking ongoing efforts at clinical translation for cancer therapy. Investigators also are developing companion CXCR4-targeted imaging agents with potential to stratify patients for CXCR4-targeted therapy and monitor treatment efficacy. Here, pre-clinical studies demonstrating functions of CXCR4 in cancer are reviewed.

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“…6,9,20 CXCR4 target therapy is being developed, which in preclinical studies has the ability to prevent tumor growth and metastatic in animal breast, head, and neck carcinoma models. 21 In small cell lung carcinoma, antagonist CXCR4 (TN14003) interferes with CXCR4-CXCL12 interactions and inhibits cell adhesion and chemoresistance. 22 In this study, the percentage of lungs metastatic (38.71%) was lower than incidence in WHO (75%).…”

Section: Discussionmentioning

confidence: 99%

Chemokine C-X-C Receptor Type 4 (CXCR4) and Autocrine Motility Factor Receptor (AMFR) expression in Renal Cell Carcinoma and Their Correlation with Metastatic in Dr Hasan Sadikin Hospital, Bandung, Indonesia

Agustina

Yulianti

Suryanti

et al. 2019

ijmsci

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Background: Renal cell carcinoma (RCC) is the most aggressive urinary tract cancer. More than one third of patients experience metastasis. Metastasis is responsible for 90% of cancer deaths compared to the primary tumor itself. Factors that play a role in the occurrence of metastasis are chemokine CXC receptors type 4 (CXCR4) and autocrine motility factor receptor (AMFR). This study aims to determine the relationship of CXCR4 and AMFR expression with metastasis in RCC. Methods: Case control research design was done to 44 Fixed Formalin Paraffin Embedded (FFPE) of RCC cases at the Department of Anatomical Pathology of Dr. Hasan Sadikin Hospital, Bandung, Indonesia. FFPE samples consist of 22 cases of metastatic RCC and 22 cases of non-metastatic RCC. Immunohistochemical staining of CXCR4 and AMFR was performed to all samples. All data were analyzed using Chi-Square test with p value < 0.05 of significant level and then processed using SPSS 24.0 for Windows. Results: The result of this study shows a significantly different statistics of CXCR4 (p = 0.015) and AMFR (p = 0.014) expression between metastatic RCC and non-metastatic RCC. AMFR expression is the stronger factor that affects metastasis compared to CXCR4 expression ((Odds Ratio AMFR : OR CXCR4 = 4,911 : 4.667). Conclusions: This study concluded that the incidence of metastatic RCC is influenced by factors of tumor cell migration, chemotaxis, and survival. The higher the CXCR4 and AMFR expression, the higher the possibility of metastasis in RCC.

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Implications of CXCR4/CXCL12 Interaction for Cancer Stem Cell Maintenance and Cancer Progression

Cited by 4 publications

References 258 publications

Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer

Chemokine C-X-C Receptor Type 4 (CXCR4) and Autocrine Motility Factor Receptor (AMFR) expression in Renal Cell Carcinoma and Their Correlation with Metastatic in Dr Hasan Sadikin Hospital, Bandung, Indonesia

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