The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development

The tumor microenvironment is a complex structure composed of the extracellular matrix (ECM) and nontumoral cells (notably cancer-associated fibroblasts (CAFs) and immune cells). Collagens are the main components of the ECM and they are extensively remodeled during tumor progression. Some collagens are ligands for the discoidin domain receptor tyrosine kinases, DDR1 and DDR2. DDRs are involved in different stages of tumor development and metastasis formation. In this review, we present the different roles of DDRs in these processes and discuss controversial findings. We conclude by describing emerging DDR inhibitory strategies, which could be used as new alternatives for the treatment of patients.

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Neutrophils as Orchestrators in Tumor Development and Metastasis Formation

Frontiers in Oncology ◽

10.3389/fonc.2020.581457 ◽

2020 ◽

Vol 10 ◽

Author(s):

Lydia Kalafati ◽

Ioannis Mitroulis ◽

Panayotis Verginis ◽

Triantafyllos Chavakis ◽

Ioannis Kourtzelis

Keyword(s):

Immune Cell ◽

Current Knowledge ◽

Tumor Development ◽

Metastasis Formation ◽

Cell Plasticity ◽

Inhibit Tumor Growth ◽

Therapeutic Modalities ◽

Mediated Effects ◽

Immune Cell Subsets ◽

Metastasis Development

Several lines of clinical and experimental evidence suggest that immune cell plasticity is a central player in tumorigenesis, tumor progression, and metastasis formation. Neutrophils are able to promote or inhibit tumor growth. Through their interaction with tumor cells or their crosstalk with other immune cell subsets in the tumor microenvironment, they modulate tumor cell survival. Here, we summarize current knowledge with regards to the mechanisms that underlie neutrophil–mediated effects on tumor establishment and metastasis development. We also discuss the tumor-mediated effects on granulopoiesis and neutrophil precursors in the bone marrow and the involvement of neutrophils in anti-tumor therapeutic modalities.

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The Interaction Between Long Non-Coding RNAs and Cancer-Associated Fibroblasts in Lung Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.714125 ◽

2022 ◽

Vol 9 ◽

Author(s):

Wenqi Ti ◽

Jianbo Wang ◽

Yufeng Cheng

Keyword(s):

Lung Cancer ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Molecular Mechanisms ◽

Tumor Development ◽

Cancer Associated Fibroblasts ◽

Protein Coding ◽

Sequencing Technologies ◽

Integral Role ◽

Tumor Growth And Metastasis

Despite great advances in research and treatment, lung cancer is still one of the most leading causes of cancer-related deaths worldwide. Evidence is mounting that dynamic communication network in the tumor microenvironment (TME) play an integral role in tumor initiation and development. Cancer-associated fibroblasts (CAFs), which promote tumor growth and metastasis, are the most important stroma component in the tumor microenvironment. Consequently, in-depth identification of relevant molecular mechanisms and biomarkers related to CAFs will increase understanding of tumor development process, which is of great significance for precise treatment of lung cancer. With the development of sequencing technologies such as microarray and next-generation sequencing, lncRNAs without protein-coding ability have been found to act as communicators between tumor cells and CAFs. LncRNAs participate in the activation of normal fibroblasts (NFs) to CAFs. Moreover, activated CAFs can influence the gene expression and secretion characteristics of cells through lncRNAs, enhancing the malignant biological process in tumor cells. In addition, lncRNA-loaded exosomes are considered to be another important form of crosstalk between tumor cells and CAFs. In this review, we focus on the interaction between tumor cells and CAFs mediated by lncRNAs in the lung cancer microenvironment, and discuss the analysis of biological function and molecular mechanism. Furthermore, it contributes to paving a novel direction for the clinical treatment of lung cancer.

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The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity

Cells ◽

10.3390/cells10092382 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2382 ◽

Cited By ~ 1

Author(s):

Jason Chekmarev ◽

Mahan Gholam Azad ◽

Des R. Richardson

Keyword(s):

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Tumor Development ◽

Pancreatic Tumors ◽

Cellular Mechanisms ◽

Oncogenic Signaling ◽

Tumor Growth And Metastasis ◽

B Lineage ◽

Cbl Protein ◽

Docking Protein

NDRG1 is an oncogenic signaling disruptor that plays a key role in multiple cancers, including aggressive pancreatic tumors. Recent studies have indicated a role for NDRG1 in the inhibition of multiple tyrosine kinases, including EGFR, c-Met, HER2 and HER3, etc. The mechanism of activity of NDRG1 remains unclear, but to impart some of its functions, NDRG1 binds directly to key effector molecules that play roles in tumor suppression, e.g., MIG6. More recent studies indicate that NDRG1s-inducing drugs, such as novel di-2-pyridylketone thiosemicarbazones, not only inhibit tumor growth and metastasis but also fibrous desmoplasia, which leads to chemotherapeutic resistance. The Casitas B-lineage lymphoma (c-Cbl) protein may be regulated by NDRG1, and is a crucial E3 ligase that regulates various protein tyrosine and receptor tyrosine kinases, primarily via ubiquitination. The c-Cbl protein can act as a tumor suppressor by promoting the degradation of receptor tyrosine kinases. In contrast, c-Cbl can also promote tumor development by acting as a docking protein to mediate the oncogenic c-Met/Crk/JNK and PI3K/AKT pathways. This review hypothesizes that NDRG1 could inhibit the oncogenic function of c-Cbl, which may be another mechanism of its tumor-suppressive effects.

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Morphological Characteristics of the Stroma in Malignat Epithelial Neoplasms with Short Review of Skin Squamous Cell Carcinoma

Macedonian Medical Review ◽

10.2478/mmr-2014-0002 ◽

2014 ◽

Vol 68 (1) ◽

pp. 8-15

Author(s):

Lena Kakasheva-Mazhenkovska ◽

Vesna Janevska ◽

Gordana Petrushevska ◽

Liljana Spasevska ◽

Neli Basheska

Keyword(s):

Immune Cells ◽

Complex Structure ◽

Tumor Development ◽

Morphological Characteristics ◽

Basal Membrane ◽

Short Review ◽

Invasion And Metastasis ◽

Genetic Changes ◽

Cancer Associated Fibroblast ◽

Skin Squamous Cell Carcinoma

Abstract The stroma of the neoplasm is a highly complex structure built by: specialized mesenchymal cells typical for each tissue surroundings, cancer associated fibroblast/myofibroblast, congenital or acquired immune cells, vascular network with endothelial cells and pericytes, mastocytes, macrophages, leukocytes and adipocytes, all together incorporated in the extracellular matrix. Each neoplasm produces its own unique microenvironment where the tumor grows and modifies. Although most of the cells of the host in the stroma have compulsory tumor suppressor ability, the stroma is changing during the malignant process and it even promotes growth, invasion and metastasis. Genetic changes that occur during the development of the cancer, which are guided by the malignant cells lead to changes in the stroma of the host that will overtake it and adjust it to their own needs. In the early stages of the tumor development and invasion, the basal membrane is degraded and the stroma becomes active and contains an increased number of fibroblasts, inflammatory infiltrate and newly composed capillaries which come into direct contact with the tumor cells. These changes lead to cancer invasion.

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Modern evolutionism and the views of A. A. Lyubishchev on the problem of species

Species in Biology - Novitates Theriologicae ◽

10.53452/nt1261 ◽

2021 ◽

pp. 371-379

Author(s):

Elena Artemieva

Keyword(s):

Related Species ◽

Homologous Series ◽

Complex Structure ◽

Huge Number ◽

Organic World ◽

Active Adaptation ◽

The Law ◽

Main Components ◽

Different Origins ◽

Adaptive Approaches

With the advent of Darwinism, historical, functional, and adaptive approaches began to dominate in the theory of form. According to A. A. Lyubishchev: «Historical morphology devoured constructive». The tasks of morphology and taxonomy are closely related. Both disciplines should strive to identify the laws governing the diversity of the organic world. The nomogenetic component of evolution, the laws underlying the system, are reflected in morphology. And vice versa, the similarity of organs of different origins, facts of incomplete homology, pre-adaptation of forms, a huge number of parallelisms and many other morphological factors prove not only the existence of laws of form, but also the nomogenetic component of evolution. Despite the heterogeneity and exceptional complexity in the structure of organisms, there is a recurrence of similar forms that penetrates the entire systematics, suggesting that the forms of organisms are not epiphenomenons of a complex structure. An excellent example of regular variability is the Law of homologous series of hereditary variability by N. I. Vavilov: «knowing what mutational changes occur in individuals of any species, one can foresee that the same mutations in similar conditions will arise in related species and genera.» For A. A. Lyubishchev, the main components of evolution were: 1) tychogenetic (evolution based on random, unforeseen mutations); 2) nomogenetic (the presence of firm laws of development and limited form formation); 3) ectogenetic (factors external to organisms); and 4) telogenetic (active adaptation of organisms). At present, the study of architectonics and promorphology is coming to the fore, i.e. symmetry of organisms.

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The Primary Cilium of Adipose Progenitors Is Necessary for Their Differentiation into Cancer-Associated Fibroblasts that Promote Migration of Breast Cancer Cells In Vitro

Cells ◽

10.3390/cells9102251 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2251

Author(s):

Pascal Peraldi ◽

Annie Ladoux ◽

Sophie Giorgetti-Peraldi ◽

Christian Dani

Keyword(s):

Breast Cancer ◽

Primary Cilium ◽

Biological Effects ◽

Tumor Development ◽

Breast Cancer Cell Lines ◽

Cancer Associated Fibroblasts ◽

Central Elements ◽

Control Tumor ◽

Tgf Β1

Cancer associated fibroblasts (CAFs) are central elements of the microenvironment that control tumor development. In breast cancer, CAFs can originate from adipose progenitors (APs). We, and others, have shown that the primary cilium, an antenna-shaped organelle, controls several aspects of APs’ biology. We studied the conversion of human APs into CAFs by breast cancer cell lines (BCCs). Deletion of the cilium of APs by a pharmacological inhibitor, or by siRNA, allow us to demonstrate that the cilium is necessary for the differentiation of APs into CAFs. BCCs increase production of TGF-β1 by APs, which is a known inducer of CAFs. Pharmacological inhibition of TGF-β1 signaling in APs prevents their conversion into CAFs. Since we previously showed that deletion of the APs’ cilium inhibits TGF-β1 signaling, we propose that BCCs induce TGF-β1 production in Aps, which binds to the primary cilium of Aps and leads to their differentiation into CAFs. Inhibition of APs conversion into CAFs induces a loss in some of the biological effects of CAFs since deletion of the cilium of APs decreases their effect on the migration of BCCs. This is the first observation of a function of the cilium of APs in their conversion into CAFs, and its consequences on BCCs.

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