Fibroblast Subsets in Intestinal Homeostasis, Carcinogenesis, Tumor Progression, and Metastasis

In intestinal homeostasis, continuous renewal of the epithelium is crucial to withstand the plethora of stimuli which can damage the structural integrity of the intestines. Fibroblasts contribute to this renewal by facilitating epithelial cell differentiation as well as providing the structural framework in which epithelial cells can regenerate. Upon dysregulation of intestinal homeostasis, (pre-) malignant neoplasms develop, a process which is accompanied by (epi) genetic alterations in epithelial cells as well as phenotypic changes in fibroblast populations. In the context of invasive carcinomas, these fibroblast populations are termed cancer-associated fibroblasts (CAFs). CAFs are the most abundant cell type in the tumor microenvironment of colorectal cancer (CRC) and consist of various functionally heterogeneous subsets which can promote or restrain cancer progression. Although most previous research has focused on the biology of epithelial cells, accumulating evidence shows that certain fibroblast subsets can also importantly contribute to tumor initiation and progression, thereby possibly providing avenues for improvement of clinical care for CRC patients. In this review, we summarized the current literature on the emerging role of fibroblasts in various stages of CRC development, ranging from adenoma initiation to the metastatic spread of cancer cells. In addition, we highlighted translational and therapeutic perspectives of fibroblasts in the different stages of intestinal tumor progression.

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Epithelial–mesenchymal transition: role in cancer progression and the perspectives of antitumor treatment

Acta Naturae ◽

10.32607/actanaturae.11010 ◽

2020 ◽

Vol 12 (3) ◽

pp. 4-23

Author(s):

A. V. Gaponova ◽

S. Rodin ◽

A. A. Mazina ◽

P. V. Volchkov

Keyword(s):

Epithelial Cells ◽

Tumor Progression ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

The Body ◽

Epithelial Tissue ◽

Mesenchymal Transition ◽

Tumor Dissemination

About 90% of all malignant tumors are of epithelial nature. The epithelial tissue is characterized by a close interconnection between cells through cellcell interactions, as well as a tight connection with the basement membrane, which is responsible for cell polarity. These interactions strictly determine the location of epithelial cells within the body and are seemingly in conflict with the metastatic potential that many cancers possess (the main criteria for highly malignant tumors). Tumor dissemination into vital organs is one of the primary causes of death in patients with cancer. Tumor dissemination is based on the so-called epithelialmesenchymal transition (EMT), a process when epithelial cells are transformed into mesenchymal cells possessing high mobility and migration potential. More and more studies elucidating the role of the EMT in metastasis and other aspects of tumor progression are published each year, thus forming a promising field of cancer research. In this review, we examine the most recent data on the intracellular and extracellular molecular mechanisms that activate EMT and the role they play in various aspects of tumor progression, such as metastasis, apoptotic resistance, and immune evasion, aspects that have usually been attributed exclusively to cancer stem cells (CSCs). In conclusion, we provide a detailed review of the approved and promising drugs for cancer therapy that target the components of the EMT signaling pathways.

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Oncogenic and Tumor Suppressive Components of the Cell Cycle in Breast Cancer Progression and Prognosis

Pharmaceutics ◽

10.3390/pharmaceutics13040569 ◽

2021 ◽

Vol 13 (4) ◽

pp. 569

Author(s):

Dharambir Kashyap ◽

Vivek Kumar Garg ◽

Elise N. Sandberg ◽

Neelam Goel ◽

Anupam Bishayee

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Epithelial Cells ◽

Cancer Progression ◽

Genetic Alterations ◽

Breast Cancer Progression ◽

Cyclin Dependent Kinase ◽

Breast Epithelial Cells ◽

Breast Epithelial ◽

Cell Cycle Machinery

Cancer, a disease of inappropriate cell proliferation, is strongly interconnected with the cell cycle. All cancers consist of an abnormal accumulation of neoplastic cells, which are propagated toward uncontrolled cell division and proliferation in response to mitogenic signals. Mitogenic stimuli include genetic and epigenetic changes in cell cycle regulatory genes and other genes which regulate the cell cycle. This suggests that multiple, distinct pathways of genetic alterations lead to cancer development. Products of both oncogenes (including cyclin-dependent kinase (CDKs) and cyclins) and tumor suppressor genes (including cyclin-dependent kinase inhibitors) regulate cell cycle machinery and promote or suppress cell cycle progression, respectively. The identification of cyclins and CDKs help to explain and understand the molecular mechanisms of cell cycle machinery. During breast cancer tumorigenesis, cyclins A, B, C, D1, and E; cyclin-dependent kinase (CDKs); and CDK-inhibitor proteins p16, p21, p27, and p53 are known to play significant roles in cell cycle control and are tightly regulated in normal breast epithelial cells. Following mitogenic stimuli, these components are deregulated, which promotes neoplastic transformation of breast epithelial cells. Multiple studies implicate the roles of both types of components—oncogenic CDKs and cyclins, along with tumor-suppressing cyclin-dependent inhibitors—in breast cancer initiation and progression. Numerous clinical studies have confirmed that there is a prognostic significance for screening for these described components, regarding patient outcomes and their responses to therapy. The aim of this review article is to summarize the roles of oncogenic and tumor-suppressive components of the cell cycle in breast cancer progression and prognosis.

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Does Subtelomeric Position of COMMD5 Influence Cancer Progression?

Frontiers in Oncology ◽

10.3389/fonc.2021.642130 ◽

2021 ◽

Vol 11 ◽

Author(s):

Carole G. Campion ◽

Thomas Verissimo ◽

Suzanne Cossette ◽

Johanne Tremblay

Keyword(s):

Tumor Progression ◽

Cancer Progression ◽

Genetic Alterations ◽

Chromosome 8 ◽

Cell Phenotype ◽

Physiological Processes ◽

Potential Link ◽

Cancer Types ◽

Oncogenic Function

The COMMD proteins are a family of ten pleiotropic factors which are widely conserved throughout evolution and are involved in the regulation of many cellular and physiological processes. COMMD proteins are mainly expressed in adult tissue and their downregulation has been correlated with tumor progression and poor prognosis in cancer. Among this family, COMMD5 emerged as a versatile modulator of tumor progression. Its expression can range from being downregulated to highly up regulated in a variety of cancer types. Accordingly, two opposing functions could be proposed for COMMD5 in cancer. Our studies supported a role for COMMD5 in the establishment and maintenance of the epithelial cell phenotype, suggesting a tumor suppressor function. However, genetic alterations leading to amplification of COMMD5 proteins have also been observed in various types of cancer, suggesting an oncogenic function. Interestingly, COMMD5 is the only member of this family that is located at the extreme end of chromosome 8, near its telomere. Here, we review some data concerning expression and role of COMMD5 and propose a novel rationale for the potential link between the subtelomeric position of COMMD5 on chromosome 8 and its contrasting functions in cancer.

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Every which way? On predicting tumor evolution using cancer progression models

10.1101/371039 ◽

2018 ◽

Cited By ~ 1

Author(s):

Ramon Diaz-Uriarte ◽

Claudia Vasallo

Keyword(s):

Tumor Progression ◽

Disease Progression ◽

Cancer Progression ◽

Genetic Alterations ◽

Fitness Landscapes ◽

Data Sets ◽

Sample Sizes ◽

Cross Sectional ◽

Cancer Data ◽

Therapeutic Decisions

AbstractSuccessful prediction of the likely paths of tumor progression is valuable for diagnostic, prognostic, and treatment purposes. Cancer progression models (CPMs) use cross-sectional samples to identify restrictions in the order of accumulation of driver mutations and thus CPMs encode the paths of tumor progression. Here we analyze the performance of four CPMs to examine whether they can be used to predict the true distribution of paths of tumor progression and to estimate evolutionary unpredictability. Employing simulations we show that if fitness landscapes are single peaked (have a single fitness maximum) there is good agreement between true and predicted distributions of paths of tumor progression when sample sizes are large, but performance is poor with the currently common much smaller sample sizes. Under multi-peaked fitness landscapes (i.e., those with multiple fitness maxima), performance is poor and improves only slightly with sample size. In all cases, detection regime (when tumors are sampled) is a key determinant of performance. Estimates of evolutionary unpredictability from the best performing CPM, among the four examined, tend to overestimate the true un-predictability and the bias is affected by detection regime; CPMs could be useful for estimating upper bounds to the true evolutionary unpredictability. Analysis of twenty-two cancer data sets shows low evolutionary unpredictability for several of the data sets. But most of the predictions of paths of tumor progression are very unreliable, and unreliability increases with the number of features analyzed. Our results indicate that CPMs could be valuable tools for predicting cancer progression but that, currently, obtaining useful predictions of paths of tumor progression from CPMs is dubious, and emphasize the need for methodological work that can account for the probably multi-peaked fitness landscapes in cancer.Author SummaryKnowing the likely paths of tumor progression is instrumental for cancer precision medicine as it would allow us to identify genetic targets that block disease progression and to improve therapeutic decisions. Direct information about paths of tumor progression is scarce, but cancer progression models (CPMs), which use as input cross-sectional data on genetic alterations, can be used to predict these paths. CPMs, however, make assumptions about fitness landscapes (genotype-fitness maps) that might not be met in cancer. We examine if four CPMs can be used to predict successfully the distribution of tumor progression paths; we find that some CPMs work well when sample sizes are large and fitness landscapes have a single fitness maximum, but in fitness landscapes with multiple fitness maxima prediction is poor. However, the best performing CPM in our study could be used to estimate evolutionary unpredictability. When we apply the best performing CPM in our study to twenty-two cancer data sets we find that predictions are generally unreliable but that some cancer data sets show low unpredictability. Our results highlight that CPMs could be valuable tools for predicting disease progression, but emphasize the need for methodological work to account for multi-peaked fitness landscapes.

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Mutated p53 in HGSC—From a Common Mutation to a Target for Therapy

Cancers ◽

10.3390/cancers13143465 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3465

Author(s):

Aya Saleh ◽

Ruth Perets

Keyword(s):

Cancer Progression ◽

Target Genes ◽

P53 Protein ◽

Genetic Alterations ◽

Common Mutation ◽

Missense Mutations ◽

P53 Expression ◽

Histologic Subtype ◽

Tp53 Mutations

Mutations in tumor suppressor gene TP53, encoding for the p53 protein, are the most ubiquitous genetic variation in human ovarian HGSC, the most prevalent and lethal histologic subtype of epithelial ovarian cancer (EOC). The majority of TP53 mutations are missense mutations, leading to loss of tumor suppressive function of p53 and gain of new oncogenic functions. This review presents the clinical relevance of TP53 mutations in HGSC, elaborating on several recently identified upstream regulators of mutant p53 that control its expression and downstream target genes that mediate its roles in the disease. TP53 mutations are the earliest genetic alterations during HGSC pathogenesis, and we summarize current information related to p53 function in the pathogenesis of HGSC. The role of p53 is cell autonomous, and in the interaction between cancer cells and its microenvironment. We discuss the reduction in p53 expression levels in tumor associated fibroblasts that promotes cancer progression, and the role of mutated p53 in the interaction between the tumor and its microenvironment. Lastly, we discuss the potential of TP53 mutations to serve as diagnostic biomarkers and detail some more advanced efforts to use mutated p53 as a therapeutic target in HGSC.

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The Role of Cancer-Associated Fibroblasts in Tumor Progression

Cancers ◽

10.3390/cancers13061399 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1399

Author(s):

Rushikesh S. Joshi ◽

Samanvi S. Kanugula ◽

Sweta Sudhir ◽

Matheus P. Pereira ◽

Saket Jain ◽

...

Keyword(s):

Cancer Treatment ◽

Tumor Progression ◽

Cancer Progression ◽

Immune Cell ◽

Systemic Disease ◽

Genomic Medicine ◽

Therapeutic Targets ◽

Therapy Resistance ◽

Cancer Associated Fibroblasts ◽

Breast Cancers

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

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Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin

Metabolites ◽

10.3390/metabo11030180 ◽

2021 ◽

Vol 11 (3) ◽

pp. 180

Author(s):

Christina Mertens ◽

Matthias Schnetz ◽

Claudia Rehwald ◽

Stephan Grein ◽

Eiman Elwakeel ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Lung Metastases ◽

Expression Profiles ◽

The Cancer Genome Atlas ◽

Lipocalin 2 ◽

Tumor Associated Macrophages

Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2−/− PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2−/− compared to wildtype tumors stored more iron. In contrast, Lcn-2−/− tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2−/− tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.

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Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽

10.3390/cancers13010068 ◽

2020 ◽

Vol 13 (1) ◽

pp. 68

Author(s):

Fulvio Massaro ◽

Florent Corrillon ◽

Basile Stamatopoulos ◽

Nathalie Meuleman ◽

Laurence Lagneaux ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Progression ◽

Cancer Progression ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Cell Communication ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Wide Range ◽

Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

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Stromal CCL5 Promotes Breast Cancer Progression by Interacting with CCR3 in Tumor Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22041918 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1918

Author(s):

Mio Yamaguchi ◽

Kiyoshi Takagi ◽

Koki Narita ◽

Yasuhiro Miki ◽

Yoshiaki Onodera ◽

...

Keyword(s):

Breast Cancer ◽

Breast Carcinoma ◽

Tumor Progression ◽

Tumor Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Human Breast Carcinoma ◽

Breast Cancer Patients ◽

Breast Carcinomas ◽

Human Breast

Chemokines secreted from stromal cells have important roles for interactions with carcinoma cells and regulating tumor progression. C-C motif chemokine ligand (CCL) 5 is expressed in various types of stromal cells and associated with tumor progression, interacting with C-C chemokine receptor (CCR) 1, 3 and 5 expressed in tumor cells. However, the expression on CCL5 and its receptors have so far not been well-examined in human breast carcinoma tissues. We therefore immunolocalized CCL5, as well as CCR1, 3 and 5, in 111 human breast carcinoma tissues and correlated them with clinicopathological characteristics. Stromal CCL5 immunoreactivity was significantly correlated with the aggressive phenotype of breast carcinomas. Importantly, this tendency was observed especially in the CCR3-positive group. Furthermore, the risk of recurrence was significantly higher in the patients with breast carcinomas positive for CCL5 and CCR3 but negative for CCR1 and CCR5, as compared with other patients. In summary, the CCL5-CCR3 axis might contribute to a worse prognosis in breast cancer patients, and these findings will contribute to a better understanding of the significance of the CCL5/CCRs axis in breast carcinoma microenvironment.

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Effect of Lipopolysaccharides (LPS) and Lipoteichoic acid (LTA) on the Inflammatory Response in Rumen Epithelial Cells (REC) and the Impact of LPS on Claw Explants

Animals ◽

10.3390/ani11072058 ◽

2021 ◽

Vol 11 (7) ◽

pp. 2058

Author(s):

Nicole Reisinger ◽

Dominik Wendner ◽

Nora Schauerhuber ◽

Elisabeth Mayer

Keyword(s):

Epithelial Cells ◽

Inflammatory Response ◽

Structural Integrity ◽

Animal Health ◽

Lipoteichoic Acid ◽

Local Inflammatory Response ◽

Tissue Integrity ◽

Separation Force ◽

The Impact ◽

Rumen Epithelial Cells

Endotoxins play a crucial role in ruminant health due to their deleterious effects on animal health. The study aimed to evaluate whether LPS and LTA can induce an inflammatory response in rumen epithelial cells. For this purpose, epithelial cells isolated from rumen tissue (RECs) were stimulated with LPS and LTA for 1, 2, 4, and 24 h. Thereafter, the expression of selected genes of the LPS and LTA pathway and inflammatory response were evaluated. Furthermore, it was assessed whether LPS affects inflammatory response and structural integrity of claw explants. Therefore, claw explants were incubated with LPS for 4 h to assess the expression of selected genes and for 24 h to evaluate tissue integrity via separation force. LPS strongly affected the expression of genes related to inflammation (NFkB, TNF-α, IL1B, IL6, CXCL8, MMP9) in RECs. LTA induced a delayed and weaker inflammatory response than LPS. In claw explants, LPS affected tissue integrity, as there was a concentration-dependent decrease of separation force. Incubation time had a strong effect on inflammatory genes in claw explants. Our data suggest that endotoxins can induce a local inflammatory response in the rumen epithelium. Furthermore, translocation of LPS might negatively impact claw health.

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