|
1
|
Ponti D. The Nucleolus: A Central Hub for Ribosome Biogenesis and Cellular Regulatory Signals. Int J Mol Sci 2025; 26:4174. [PMID: 40362410 DOI: 10.3390/ijms26094174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/18/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The nucleolus is the most prominent nuclear domain in eukaryotic cells, primarily responsible for ribosome biogenesis. It synthesizes and processes precursor ribosomal RNA (pre-rRNA) into mature rRNAs, assembling the 40S and 60S ribosomal subunits, which later form the 80S ribosome-the essential molecular machine for protein synthesis. Beyond ribosome production, the nucleolus lacks a delimiting membrane, allowing it to rapidly regulate cellular homeostasis by sequestering key stress response factors. This adaptability enables dynamic changes in size, number, and protein composition in response to cellular stress and signaling. Recent research highlights the nucleolus as a critical regulator of chemoresistance. Given its central role in cell survival and stress adaptation, the nucleolus has become an attractive therapeutic target, particularly in cancer treatment. A deeper understanding of nucleolar metabolism could pave the way for novel therapeutic strategies against various human diseases.
Collapse
Affiliation(s)
- Donatella Ponti
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso Della Repubblica 79, 04100 Latina, Italy
| |
Collapse
|
|
2
|
Zhang D, Zhang Y, Zou X, Li M, Zhang H, Du Y, Wang J, Peng C, Dong C, Hou Z. CHST2-mediated sulfation of MECA79 antigens is critical for breast cancer cell migration and metastasis. Cell Death Dis 2023; 14:288. [PMID: 37095090 PMCID: PMC10126008 DOI: 10.1038/s41419-023-05797-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 04/26/2023]
Abstract
Snail is a denoted transcriptional repressor that plays key roles in epithelial-mesenchymal transition (EMT) and metastasis. Lately, a plethora of genes can be induced by stable expression of Snail in multiple cell lines. However, the biological roles of these upregulated genes are largely elusive. Here, we report identification of a gene encoding the key GlcNAc sulfation enzyme CHST2 is induced by Snail in multiple breast cancer cells. Biologically, CHST2 depletion results in inhibition of breast cancer cell migration and metastasis, while overexpression of CHST2 promotes cell migration and lung metastasis in nude mice. In addition, the expression level of MECA79 antigen is elevated and blocking the cell surface MECA79 antigen with specific antibodies can override cell migration mediated by CHST2 upregulation. Moreover, the sulfation inhibitor sodium chlorate effectively inhibits the cell migration induced by CHST2. Collectively, these data provide novel insights into the biology of Snail/CHST2/MECA79 axis in breast cancer progression and metastasis as well as potential therapeutic strategy for the diagnosis and treatment of breast cancer metastasis.
Collapse
Affiliation(s)
- Dan Zhang
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Breast Cancer Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yihong Zhang
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiuqun Zou
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mengying Li
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hui Zhang
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yaning Du
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jiamin Wang
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chicheng Peng
- Shandong NARUI Biotechnology Co., LTD, Shandong, China
| | - Chunyan Dong
- Breast Cancer Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - Zhaoyuan Hou
- Hongqiao Institute of Medicine, Tongren Hospital/Faculty of Basic Medicine, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
3
|
Guo Y, Wang S, Zhao ZY, Li JN, Shang A, Li DL, Wang M. Skeletal muscle metastasis with bone metaplasia from colon cancer: A case report and review of the literature. World J Clin Cases 2021; 9:9285-9294. [PMID: 34786415 PMCID: PMC8567510 DOI: 10.12998/wjcc.v9.i30.9285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/30/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colon cancer is a common malignant disease of the gastrointestinal tract and usually occurs at the junction of the rectum and sigmoid colon. Lymphatic and hematogenous metastases occur frequently in colon cancer and the most common metastatic sites include the liver, lung, peritoneum, bone, and lymph nodes. As a manifestation of advanced tumor spread and metastasis, soft tissue metastasis, especially skeletal muscle metastasis with bone metaplasia caused by colon cancer, is rare, accounting for less than 1% of metastases.
CASE SUMMARY A 43-year-old male patient developed skeletal muscle metastasis with bone metaplasia of the right proximal thigh 5 mo after colon cancer was diagnosed. The patient was admitted to the hospital because of pain caused by a local mass on his right thigh. Positron emission tomography-computed tomography showed many enlarged lymph nodes around the abdominal aorta but no signs of lung or liver metastases. Color ultrasound revealed a mass located in the skeletal muscle and the results of histological biopsy revealed a poorly differentiated adenocarcinoma suspected to be distant metastases from colon cancer. Immunohistochemistry showed small woven bone components that were considered to be ossified.
CONCLUSION This case reminds us that for patients with advanced colorectal tumors, we should be alert to the possibility of unconventional metastasis.
Collapse
Affiliation(s)
- Yu Guo
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Shuang Wang
- Department of Dermatology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Ze-Yun Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - An Shang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Dong-Lin Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Min Wang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| |
Collapse
|
|
4
|
Liu S, Wu D, Sun X, Fan Y, Zha R, Jalali A, Feng Y, Li K, Sano T, Vike N, Li F, Rispoli J, Sudo A, Liu J, Robling A, Nakshatri H, Li BY, Yokota H. Overexpression of Lrp5 enhanced the anti-breast cancer effects of osteocytes in bone. Bone Res 2021; 9:32. [PMID: 34230453 PMCID: PMC8260600 DOI: 10.1038/s41413-021-00152-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 02/22/2021] [Accepted: 03/28/2021] [Indexed: 02/07/2023] Open
Abstract
Osteocytes are the most abundant cells in bone, which is a frequent site of breast cancer metastasis. Here, we focused on Wnt signaling and evaluated tumor-osteocyte interactions. In animal experiments, mammary tumor cells were inoculated into the mammary fat pad and tibia. The role of Lrp5-mediated Wnt signaling was examined by overexpressing and silencing Lrp5 in osteocytes and establishing a conditional knockout mouse model. The results revealed that administration of osteocytes or their conditioned medium (CM) inhibited tumor progression and osteolysis. Osteocytes overexpressing Lrp5 or β-catenin displayed strikingly elevated tumor-suppressive activity, accompanied by downregulation of tumor-promoting chemokines and upregulation of apoptosis-inducing and tumor-suppressing proteins such as p53. The antitumor effect was also observed with osteocyte-derived CM that was pretreated with a Wnt-activating compound. Notably, silencing Lrp5 in tumors inhibited tumor progression, while silencing Lrp5 in osteocytes in conditional knockout mice promoted tumor progression. Osteocytes exhibited elevated Lrp5 expression in response to tumor cells, implying that osteocytes protect bone through canonical Wnt signaling. Thus, our results suggest that the Lrp5/β-catenin axis activates tumor-promoting signaling in tumor cells but tumor-suppressive signaling in osteocytes. We envision that osteocytes with Wnt activation potentially offer a novel cell-based therapy for breast cancer and osteolytic bone metastasis.
Collapse
Affiliation(s)
- Shengzhi Liu
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.
| | - Di Wu
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China.,Department of Pharmacy, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xun Sun
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Yao Fan
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Rongrong Zha
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Aydin Jalali
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Yan Feng
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Kexin Li
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Tomohiko Sano
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Orthopedic Surgery, Mie University, Tsu, Mie, Japan
| | - Nicole Vike
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Fangjia Li
- Department of Physics, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Joseph Rispoli
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Akihiro Sudo
- Department of Orthopedic Surgery, Mie University, Tsu, Mie, Japan
| | - Jing Liu
- Department of Physics, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Alexander Robling
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Harikrishna Nakshatri
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.,Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Bai-Yan Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Hiroki Yokota
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA. .,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China. .,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA. .,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA. .,Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
| |
Collapse
|
|
5
|
Tian X, Yu H, Li D, Jin G, Dai S, Gong P, Kong C, Wang X. The miR-5694/AF9/Snail Axis Provides Metastatic Advantages and a Therapeutic Target in Basal-like Breast Cancer. Mol Ther 2021; 29:1239-1257. [PMID: 33221433 PMCID: PMC7934584 DOI: 10.1016/j.ymthe.2020.11.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/30/2020] [Accepted: 11/15/2020] [Indexed: 02/07/2023] Open
Abstract
Epigenetic deregulation, especially mutagenesis or the abnormal expression of epigenetic regulatory factors (ERFs), plays an important role in malignant tumorigenesis. To screen natural inhibitors of breast cancer metastasis, we adopted small interfering RNAs (siRNAs) to transiently knock down 591 ERF-coding genes in luminal breast cancer MCF-7 cells and found that depletion of AF9 significantly promoted MCF-7 cell invasion and migration. A mouse model of metastasis further confirmed the suppressive role of AF9 in breast cancer metastasis. RNA profiling revealed enrichment of AF9 targets genes in the epithelial-mesenchymal transition (EMT). Mechanistically, tandem mass spectrometry showed that AF9 interacts with Snail, which hampers Snail transcriptional activity in basal-like breast cancer (BLBC) cells. AF9 reconstitutes an activated state on the promoter of Snail, which is a master regulator of EMT, and derepresses genes by recruiting CBP or GCN5. Additionally, microRNA-5694 (miR-5694) targeted and degraded AF9 messenger RNA (mRNA) in BLBC cells, further enhancing cell invasion and migration. Notably, AF9 and miR-5694 expression in BLBC clinical samples correlated inversely. Hence, miR-5694 mediates downregulation of AF9 and provides metastatic advantages in BLBC. Restoring expression of the metastasis suppressor AF9 is a possible therapeutic strategy against metastatic breast cancer.
Collapse
MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Carcinoma, Basal Cell/genetics
- Carcinoma, Basal Cell/metabolism
- Carcinoma, Basal Cell/pathology
- Cell Proliferation
- Epithelial-Mesenchymal Transition
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/secondary
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- Neoplasm Invasiveness
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Prognosis
- RNA, Small Interfering/genetics
- Snail Family Transcription Factors/genetics
- Snail Family Transcription Factors/metabolism
- Survival Rate
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
Collapse
Affiliation(s)
- Xin Tian
- Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang, China; Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510006, China.
| | - Hua Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510006, China
| | - Dong Li
- International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, The China Welfare Institute, Shanghai 200030, China
| | - Guojiang Jin
- Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Shundong Dai
- Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China
| | - Pengchao Gong
- Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Cuicui Kong
- Cancer Research Institute, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xiongjun Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510006, China.
| |
Collapse
|
|
6
|
Liu S, Wu D, Sun X, Fan Y, Zha R, Jalali A, Teli M, Sano T, Siegel A, Sudo A, Agarwal M, Robling A, Li BY, Yokota H. Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1. FASEB J 2020; 34:12847-12859. [PMID: 32744779 DOI: 10.1096/fj.202000713rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 07/09/2020] [Accepted: 07/17/2020] [Indexed: 12/27/2022]
Abstract
Mechanical stimulations can prevent bone loss, but their effects on the tumor-invaded bone or solid tumors are elusive. Here, we evaluated the effect of knee loading, dynamic loads applied to the knee, on metastasized bone and mammary tumors. In a mouse model, tumor cells were inoculated to the mammary fat pad or the proximal tibia. Daily knee loading was then applied and metabolic changes were monitored mainly through urine. Urine samples were also collected from human subjects before and after step aerobics. The result showed that knee loading inhibited tumor progression in the loaded tibia. Notably, it also reduced remotely the growth of mammary tumors. In the urine, an altered level of cholesterol was observed with an increase in calcitriol, which is synthesized from a cholesterol derivative. In urinary proteins, knee loading in mice and step aerobics in humans markedly reduced WNT1-inducible signaling pathway protein 1, WISP1, which leads to poor survival among patients with breast cancer. In the ex vivo breast cancer tissue assay, WISP1 promoted the growth of cancer fragments and upregulated tumor-promoting genes, such as Runx2, MMP9, and Snail. Collectively, the present preclinical and human study demonstrated that mechanical stimulations, such as knee loading and step aerobics, altered urinary metabolism and downregulated WISP1. The study supports the benefit of mechanical stimulations for locally and remotely suppressing tumor progression. It also indicated the role of WISP1 downregulation as a potential mechanism of loading-driven tumor suppression.
Collapse
Affiliation(s)
- Shengzhi Liu
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Di Wu
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Xun Sun
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Yao Fan
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Rongrong Zha
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Aydin Jalali
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Meghana Teli
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Tomohiko Sano
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Orthopedic Surgery, Mie University, Mie, Japan
| | - Amanda Siegel
- Integrated Nanosystems Development Institute, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Akihiro Sudo
- Department of Orthopedic Surgery, Mie University, Mie, Japan
| | - Mangilal Agarwal
- Integrated Nanosystems Development Institute, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Mechanical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA
| | - Alexander Robling
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Bai-Yan Li
- Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China
| | - Hiroki Yokota
- Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Pharmacology, School of Pharmacy, Harbin Medical University, Harbin, China.,Integrated Nanosystems Development Institute, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Mechanical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN, USA.,Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.,Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA
| |
Collapse
|
|
7
|
Henderson VM, Hawsawi O, Burton LJ, Campbell T, Trice K, Dougan J, Howard SM, Odero-Marah VA. Cancer-bone microenvironmental interactions promotes STAT3 signaling. Mol Carcinog 2019; 58:1349-1361. [PMID: 31045290 DOI: 10.1002/mc.23019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 03/22/2019] [Accepted: 03/29/2019] [Indexed: 12/30/2022]
Abstract
Prostate cancer (PCa) patients' mortality is mainly attributed to complications caused by metastasis of the tumor cells to organs critical for survival, such as bone. We hypothesized that PCa cell-bone interactions would promote paracrine signaling. A panel of PCa cell lines were cocultured with hydroxyapatite ([HA]; inorganic component of bone) of different densities. Conditioned media (CM) was collected and analyzed for calcium levels and effect on paracrine signaling, cell migration, and viability in vitro and in vivo. Our results showed that calcium levels were elevated in CM from cancer cell-bone cocultures, compared to media or cancer cells alone, and this could be antagonized by ethylene glycol-bis(2-aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA), a calcium chelator, or knockdown of Snail protein. We also observed increased signal transducer and activator of transcription 3 (STAT3) phosphorylation and paracrine cell proliferation and migration in LNCaP cells incubated with CM from various cell lines; this phosphorylation and cell migration could be antagonized by Snail knockdown or various inhibitors including EGTA, STAT3 inhibitor (WP1066) or cathepsin L inhibitor (Z-FY-CHO). In vivo, higher HA bone density increased tumorigenicity and migration of tumor cells to HA implant. Our study shows that cancer-bone microenvironment interactions lead to calcium-STAT3 signaling, which may present an area for therapeutic targeting of metastatic PCa.
Collapse
Affiliation(s)
- Veronica M Henderson
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Ohuod Hawsawi
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Liza J Burton
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Taaliah Campbell
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Kennedi Trice
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Jodi Dougan
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Simone M Howard
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Valerie A Odero-Marah
- Department of Biological Sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| |
Collapse
|
|
8
|
Mitchell B, Dhingra JK, Mahalingam M. BRAF and Epithelial-Mesenchymal Transition: Lessons From Papillary Thyroid Carcinoma and Primary Cutaneous Melanoma. Adv Anat Pathol 2016; 23:244-71. [PMID: 27145091 DOI: 10.1097/pap.0000000000000113] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The increased prevalence of BRAF mutations in thyroid carcinoma and primary cutaneous melanoma (PCM) hint that dysregulation of BRAF might contribute to the noted association between PCM and thyroid carcinoma. A recent study evaluating the rate of BRAFV600E mutations among patients who had been diagnosed with primary papillary thyroid carcinoma (PTC) and PCM showed that patients with either PCM or PTC were at an increased risk of developing the other as a second primary malignant neoplasm. Furthermore, the authors noted that samples from patients suffering from both malignancies exhibited a higher rate of incidence of the BRAFV600E mutation, compared with patients not suffering from both malignancies. These studies support the hypothesis that the pathogenesis of these 2 malignancies might share a conserved molecular pattern associated with dysregulation of the BRAF protein. One mechanism through which BRAF might contribute to PCM and thyroid carcinoma progression is through induction of epithelial-mesenchymal transition (EMT). Specifically, the Snail/E-cadherin axis has been demonstrated as a pathway dysregulated by BRAF, leading to EMT in both malignancies. Our analysis focuses on the results of these recent investigations, and through a review of select molecules relevant to EMT, looks to provide a context by which to better understand the relevance and role of stromal-parenchymal signaling and the BRAF mutation in the pathogenesis of PTC and PCM.
Collapse
Affiliation(s)
- Brendon Mitchell
- *University of Florida College of Medicine, Gainesville, FL †Department of Otolaryngology, Tufts Medical center, Boston, MA ‡Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA Consolidated Laboratories, West Roxbury, MA
| | | | | |
Collapse
|
|
9
|
Habibi L, Pedram M, AmirPhirozy A, Bonyadi K. Mobile DNA Elements: The Seeds of Organic Complexity on Earth. DNA Cell Biol 2015. [DOI: 10.1089/dna.2015.2938] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Laleh Habibi
- Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Nutrition Department, School of Nutritional Science and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Pedram
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Akbar AmirPhirozy
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Khadijeh Bonyadi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
10
|
Henderson V, Smith B, Burton LJ, Randle D, Morris M, Odero-Marah VA. Snail promotes cell migration through PI3K/AKT-dependent Rac1 activation as well as PI3K/AKT-independent pathways during prostate cancer progression. Cell Adh Migr 2015. [PMID: 26207671 DOI: 10.1080/19336918.2015.1013383] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Snail, a zinc-finger transcription factor, induces epithelial-mesenchymal transition (EMT), which is associated with increased cell migration and metastasis in cancer cells. Rac1 is a small G-protein which upon activation results in formation of lamellipodia, the first protrusions formed by migrating cells. We have previously shown that Snail promotes cell migration through down-regulation of maspin tumor suppressor. We hypothesized that Snail's regulation of cell migration may also involve Rac1 signaling regulated by PI3K/AKT and/or MAPK pathways. We found that Snail overexpression in LNCaP and 22Rv1 prostate cancer cells increased Rac1 activity associated with increased cell migration, and the Rac1 inhibitor, NSC23766, could inhibit Snail-mediated cell migration. Conversely, Snail downregulation using shRNA in the aggressive C4-2 prostate cancer cells decreased Rac1 activity and cell migration. Moreover, Snail overexpression increased ERK and PI3K/AKT activity in 22Rv1 prostate cancer cells. Treatment of Snail-overexpressing 22Rv1 cells with LY294002, PI3K/AKT inhibitor or U0126, MEK inhibitor, decreased cell migration significantly, but only LY294002 significantly reduced Rac1 activity, suggesting that Snail promotes Rac1 activation via the PI3K/AKT pathway. Furthermore, 22Rv1 cells overexpressing Snail displayed decreased maspin levels, while inhibition of maspin expression in 22Rv1 cells with siRNA, led to increased PI3K/AKT, Rac1 activity and cell migration, without affecting ERK activity, suggesting that maspin is upstream of PI3K/AKT. Overall, we have dissected signaling pathways by which Snail may promote cell migration through MAPK signaling or alternatively through PI3K/AKT-Rac1 signaling that involves Snail inhibition of maspin tumor suppressor. This may contribute to prostate cancer progression.
Collapse
Affiliation(s)
- Veronica Henderson
- a Center for Cancer Research and Therapeutic Development; Department of Biological Sciences ; Clark Atlanta University ; Atlanta , GA USA
| | | | | | | | | | | |
Collapse
|
|
11
|
Zhang Y, Fan N, Yang J. Expression and clinical significance of hypoxia-inducible factor 1α, Snail and E-cadherin in human ovarian cancer cell lines. Mol Med Rep 2015; 12:3393-3399. [PMID: 25975373 PMCID: PMC4526076 DOI: 10.3892/mmr.2015.3786] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/14/2015] [Indexed: 12/13/2022] Open
Abstract
The aim of the present study was to investigate the expression and clinical significance of hypoxia-inducible factor 1α (HIF-1α), Snail and E-cadherin in ovarian cancer. The expression levels were assessed in a number of ovarian cancer cell lines and ovarian cancer tissues, and correlations between the expression of the three proteins and clinical pathological factors were analyzed. Transwell assays showed that the invasive ability of the ovarian cancer cell lines SKOV3 and ES‑2 were significantly higher than those of TYK and 3AO (P<0.01). Furthermore, the expression levels of HIF‑1α and Snail in SKOV3 and ES‑2 were significantly higher than those in TYK and 3AO, whereas the expression levels of E‑cadherin in SKOV3 and ES‑2 were significantly lower than those in TYK and 3AO (P<0.05). In ovarian cancer tissues, the expression levels of HIF‑1α, Snail and E‑cadherin were correlated with clinical pathological factors (P<0.01); furthermore, there was a positive correlation between the expression levels of HIF‑1α and Snail (r=0.231; P=0.021), and a negative correlation between the expression levels of Snail and that of E‑cadherin (r=‑0.225; P=0.028). HIF‑1α was suggested to be able to suppress the expression of E‑cadherin by upregulating Snail, thus serving an important role in invasion and metastasis of ovarian cancer.
Collapse
Affiliation(s)
- Yan Zhang
- Department of Gynaecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Nina Fan
- Department of Gynaecology and Obstetrics, Hubei Xinhau Hospital, Wuhan, Hubei 430060, P.R. China
| | - Jing Yang
- Department of Gynaecology and Obstetrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| |
Collapse
|
|
12
|
Regulation of MDA-MB-231 cell proliferation by GSK-3β involves epigenetic modifications under high glucose conditions. Exp Cell Res 2014; 324:75-83. [DOI: 10.1016/j.yexcr.2014.03.019] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Revised: 01/09/2014] [Accepted: 03/25/2014] [Indexed: 11/24/2022]
|
|
13
|
Epidermal Snail expression drives skin cancer initiation and progression through enhanced cytoprotection, epidermal stem/progenitor cell expansion and enhanced metastatic potential. Cell Death Differ 2013; 21:310-20. [PMID: 24162662 DOI: 10.1038/cdd.2013.148] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 08/29/2013] [Accepted: 09/13/2013] [Indexed: 12/17/2022] Open
Abstract
Expression of the EMT-inducing transcription factor Snail is enhanced in different human cancers. To investigate the in vivo role of Snail during progression of epithelial cancer, we used a mouse model with skin-specific overexpression of Snail. Snail transgenic mice spontaneously developed distinct histological subtypes of skin cancer, such as basal cell carcinoma, squamous cell carcinoma and sebaceous gland carcinoma. Development of sebaceous gland carcinomas strongly correlated with the direct and complete repression of Blimp-1, a central regulator of sebocyte homeostasis. Snail expression in keratinocyte stem cells significantly promotes their proliferation associated with an activated FoxM1 gene expression signature, resulting in a larger pool of Mts24-marked progenitor cells. Furthermore, primary keratinocytes expressing Snail showed increased survival and strong resistance to genotoxic stress. Snail expression in a skin-specific p53-null background resulted in accelerated formation of spontaneous tumours and enhanced metastasis. Our data demonstrate that in vivo expression of Snail results in de novo epithelial carcinogenesis by allowing enhanced survival, expansion of the cancer stem cell pool with accumulated DNA damage, a block in terminal differentiation and increased proliferation rates of tumour-initiating cells.
Collapse
|
|
14
|
Mittal MK, Myers JN, Bailey CK, Misra S, Chaudhuri G. Mode of action of the retrogene product SNAI1P, a SNAIL homolog, in human breast cancer cells. Mol Biol Rep 2009; 37:1221-7. [PMID: 19277896 DOI: 10.1007/s11033-009-9492-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Accepted: 02/24/2009] [Indexed: 01/16/2023]
Abstract
SNAI1P, a protein coded by a retrogene, is a member of the SNAI family of E2-box binding transcriptional repressors. To evaluate whether the mode of action of SNAI1P is similar to those of the other predominant members of the SNAI family, we studied its action on human claudin 7 (CLDN7) gene promoter which has seven E2-boxes. We over-expressed FLAG-tagged SNAI1P in MCF7 and MDA-MB-468 cells. SNAI1P inhibited the expression of CLDN7 in these recombinant cells. SNAI1P also inhibited cloned CLDN7 gene promoter activity in human breast cancer cells. ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1. Treatment of the cells with trichostatin A, an inhibitor of HDAC1, abrogated the repressor activity of SNAI1P. These data suggest that SNAI1P inhibits CLDN7 gene promoter epigenetically in breast cancer cells through chromatin remodeling.
Collapse
Affiliation(s)
- Mukul K Mittal
- Department of Microbial Pathogenesis and Immune Response, Meharry Medical College, Nashville, TN 37208, USA
| | | | | | | | | |
Collapse
|
|
15
|
Blocking of p53-Snail binding, promoted by oncogenic K-Ras, recovers p53 expression and function. Neoplasia 2009; 11:22-31, 6p following 31. [PMID: 19107228 DOI: 10.1593/neo.81006] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2008] [Revised: 10/18/2008] [Accepted: 10/20/2008] [Indexed: 01/13/2023] Open
Abstract
Differentially from other kinds of Ras, oncogenic K-Ras, which is mutated approximately 30% of human cancer, does not induce apoptosis and senescence. Here, we provide the evidence that oncogenic K-Ras abrogates p53 function and expression through induction of Ataxia telangiectasia-mutated and Rad3-related mediated Snail stabilization. Snail directly binds to DNA binding domain of p53 and diminishes the tumor-suppressive function of p53. Thus, elimination of Snail through si-RNA can induce p53 in K-Ras-mutated cells, whereas Snail and mutant K-Ras can suppress p53 in regardless of K-Ras status. Chemicals, isolated from inhibitor screening of p53-Snail binding, can block the Snail-mediated p53 suppression and enhance the expression of p53 as well as the transcriptional activity of p53 in an oncogenic K-Ras-dependent manner. Among the chemicals, two are very similar in structure. These results can answer why K-Ras can coexist with wild type p53 and propose the Snail-p53 binding as the new therapeutic target for K-Ras-mutated cancers including pancreatic, lung, and colon cancers.
Collapse
|
|
16
|
McPhee TR, McDonald PC, Oloumi A, Dedhar S. Integrin-linked kinase regulates E-cadherin expression through PARP-1. Dev Dyn 2008; 237:2737-47. [PMID: 18773488 DOI: 10.1002/dvdy.21685] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Repression of E-cadherin expression by the transcription factor, Snail, is implicated in epithelial to mesenchymal transition and cancer progression. We show here that Integrin-Linked Kinase (ILK) regulates E-cadherin expression through Poly(ADP-ribose) polymerase-1 (PARP-1). ILK overexpression in Scp2 cells resulted in stimulation of Snail expression and loss of E-cadherin expression. Silencing of ILK, Akt or Snail resulted in re-expression of E-cadherin in PC3 cells. To elucidate the signaling pathway downstream of ILK, we identified candidate Snail promoter ILK Responsive Element (SIRE) binding proteins. PARP-1 was identified as a SIRE-binding protein. ILK silencing inhibited binding of PARP-1 to SIRE. PARP-1 silencing resulted in inhibition of Snail and ZEB1, leading to up-regulation of E-cadherin. We suggest a model in which ILK represses E-cadherin expression by regulating PARP-1, leading to the binding of PARP-1 to SIRE and modulation of Snail expression.
Collapse
Affiliation(s)
- Timothy R McPhee
- Genetics Graduate Program, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
| | | | | | | |
Collapse
|
|
17
|
Waldmann J, Feldmann G, Slater EP, Langer P, Buchholz M, Ramaswamy A, Saeger W, Rothmund M, Fendrich V. Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival. Br J Cancer 2008; 99:1900-7. [PMID: 19018264 PMCID: PMC2600683 DOI: 10.1038/sj.bjc.6604755] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
In this study, we evaluate whether Snail is expressed in adrenocortical cancer (ACC) and if its expression is related to patient outcome. One of the best known functions of the zinc-finger transcription factor Snail is to induce epithelial-to-mesenchymal transition (EMT). Increasing evidence suggests that EMT plays a pivotal role in tumour progression and metastatic spread. Snail and E-cadherin expression were assessed by immunohistochemistry in 26 resected ACCs and real-time quantitative RT–PCR expression analysis was performed. Data were correlated with clinical outcome and in particular with overall patient survival. Seventeen of 26 (65%) ACC tumour samples expressed Snail when assessed by immunohistochemistry. Snail expression was neither detected in normal adrenocortical tissue, nor in benign adrenocortical adenomas. Expression levels were confirmed on the mRNA level by Real-Time–PCR. Survival rates were significantly decreased in Snail-positive tumours compared to Snail-negative tumours: 10 out of 16 vs one out of eight patients succumbed to disease after a median follow up of 14.5 and 28.5 months, respectively (P=0.03). Patients with Snail-expressing ACCs presented in advanced disease (11 out of 12 vs 6 out of 14, P=0.01) and tend to develop distant metastases more frequently than patients with negative staining (7 out of 11 vs two out of eight, P=0.19). In conclusion, we describe for the first time that Snail is expressed in a large subset of ACCs. Furthermore, Snail expression is associated with decreased survival, advanced disease and higher risk of developing distant metastases.
Collapse
Affiliation(s)
- J Waldmann
- Department of Surgery, Philipps-Universität Marburg, Marburg, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Abstract
Invasive lobular carcinoma (ILC) and lobular carcinoma in situ characteristically show loss of E-cadherin expression and so immunohistochemistry for E-cadherin is being increasingly used as a tool to differentiate between lobular and ductal lesions in challenging situations. However, misinterpretation of "aberrant" positive staining may lead some to exclude a diagnosis of lobular carcinoma. E-cadherin and beta-catenin immunohistochemistry was analyzed in 25 ILCs. E-cadherin "positive" ILCs were subjected to molecular analysis including comparative genomic hybridization. Different morphologic components of case 25, showing heterogenous E-cadherin expression, were analyzed by E-cadherin gene sequencing, methylation, and DASL gene expression profiling. Four ILCs were positive for E-cadherin, but each also had neoplastic cells with aberrant staining. Two of these ILCs were positive for beta-catenin, again with some aberrantly stained neoplastic cells, and 2 were negative. The solid component of case 25 was positive for E-cadherin whereas the classic and alveolar areas were negative. All components harbored an in-frame deletion in exon 7 (867del24) of the E-cadherin gene and loss of the wild type allele. Comparative genomic hybridization demonstrated evidence of clonal evolution from E-cadherin-positive to E-cadherin-negative components. E-cadherin down-regulation seems to be through transcriptional repression via activation of transforming growth factor-beta/SMAD2 rather than methylation. Positive staining for E-cadherin should not preclude a diagnosis of lobular in favor of ductal carcinoma. Molecular evidence suggests that even when E-cadherin is expressed, the cadherin-catenin complex maybe nonfunctional. Misclassification of tumors may lead to mismanagement of patients in clinical practice, particularly in the context of in situ disease at margins.
Collapse
|
|
19
|
Baum B, Settleman J, Quinlan MP. Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 2008; 19:294-308. [PMID: 18343170 DOI: 10.1016/j.semcdb.2008.02.001] [Citation(s) in RCA: 298] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2008] [Accepted: 02/04/2008] [Indexed: 12/21/2022]
Abstract
The ancestors of modern Metazoa were constructed in large part by the foldings and distortions of two-dimensional sheets of epithelial cells. This changed approximately 600 million years ago with the evolution of mesenchymal cells. These cells arise as the result of epithelial cell delamination through a reprogramming process called an epithelial to mesenchymal transition (EMT) [Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev 2003;120:1351-83; Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131-42]. Because mesenchymal cells are free to migrate through the body cavity, the evolution of the mesenchyme opened up new avenues for morphological plasticity, as cells evolved the ability to take up new positions within the embryo and to participate in novel cell-cell interactions; forming new types of internal tissues and organs such as muscle and bone [Thiery JP, Sleeman, JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131-42; Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 1995;26:678-90]. After migrating to a suitable site, mesenchymal cells coalesce and re-polarize to form secondary epithelia, in a so-called mesenchymal-epithelial transition (MET). Such switches between mesenchymal and epithelial states are a frequent feature of Metazoan gastrulation [Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 1995;26:678-90] and the neural crest lineage [Duband JL, Monier F, Delannet M, Newgreen D. Epitheliu-mmesenchyme transition during neural crest development. Acta Anat 1995;154:63-78]. Significantly, however, when hijacked during the development of cancer, the ability of cells to undergo EMT, to leave the primary tumor and to undergo MET at secondary sites can have devastating consequences on the organism, allowing tumor cells derived from epithelia to invade surrounding tissues and spread through the host [Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006;7:131-42; Hay ED, Zuk A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am J Kidney Dis 1995;26:678-90]. Thus, the molecular and cellular mechanisms underpinning EMT are both an essential feature of Metazoan development and an important area of biomedical research. In this review, we discuss the common molecular and cellular mechanisms involved in EMT in both cases.
Collapse
Affiliation(s)
- Buzz Baum
- Department of Cell and Developmental Biology, UCL, London, UK
| | | | | |
Collapse
|
|
20
|
Abstract
Invasion, the hallmark of malignancy, consists in the translocation of tumour cells from the initial neoplastic focus into neighbouring host tissues, and also allows tumour cells to penetrate vessel endothelium and enter the circulation to form distant metastasis. A histological pattern found at the periphery of carcinomas is the presence of individual malignant cells detached from the tumour mass and staying independently within the interstitial matrix of the stroma. While they are readily identified by the pathologist as invading malignant cells, their relationship with the compact-appearing portions of the tumour as well as the mechanism underlying the development of this pattern are not immediately evident at histological level. There is growing evidence suggesting that this change in tumour tissue architecture takes place through a peculiar phenotype modulation known as epithelial-mesenchymal transition (EMT). The essential features of EMT are the disruption of intercellular contacts and the enhancement of cell motility, thereby leading to the release of cells from the parent epithelial tissue. The resulting mesenchymal-like phenotype is suitable for migration and, thus, for tumour invasion and dissemination, allowing metastatic progression to proceed. Although the molecular bases of EMT have not been completely elucidated, several interconnected transduction pathways and a number of signalling molecules potentially involved have been identified. These include growth factors, receptor tyrosine kinases, Ras and other small GTPases, Src, beta-catenin and integrins. Most of these pathways converge on the down-regulation of the epithelial molecule E-cadherin, an event critical in tumour invasion and a 'master' programmer of EMT. E-cadherin gene is somatically inactivated in many diffuse-type cancers such as lobular carcinoma of the breast and diffuse gastric carcinoma, in which neoplastic cells through the entire tumour mass have lost many of their epithelial characteristics and exhibit a highly invasive, EMT-derived histological pattern. E-cadherin down-modulation is also seen in solid, non-diffuse-type cancers at the tumour-stroma boundary where singly invading, EMT-derived tumour cells are seen in histological sections. In this latter scenario, E-cadherin loss and EMT could be transient, reversible processes possibly regulated by the tumour microenvironment and, as a matter of fact, neoplastic cells that have undergone EMT during invasion seem to regain E-cadherin expression and their epithelial, cohesive characteristics at the secondary foci. Since the molecules involved in EMT represent potential targets for pharmacological agents, these findings open new avenues for the control of metastatic spread in the treatment of malignancies.
Collapse
Affiliation(s)
- Marcello Guarino
- Department of Anatomical Pathology, Hospital of Vimercate. Milan, Italy.
| | | | | |
Collapse
|
|
21
|
Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7:415-28. [PMID: 17508028 DOI: 10.1038/nrc2131] [Citation(s) in RCA: 2478] [Impact Index Per Article: 137.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The molecular mechanisms that underlie tumour progression are still poorly understood, but recently our knowledge of particular aspects of some of these processes has increased. Specifically, the identification of Snail, ZEB and some basic helix-loop-helix (bHLH) factors as inducers of epithelial-mesenchymal transition (EMT) and potent repressors of E-cadherin expression has opened new avenues of research with potential clinical implications.
Collapse
Affiliation(s)
- Héctor Peinado
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
| | | | | |
Collapse
|