scholarly journals Mutant p53—a potential player in shaping the tumor–stroma crosstalk

2019 ◽  
Vol 11 (7) ◽  
pp. 600-604 ◽  
Author(s):  
Yan Stein ◽  
Ronit Aloni-Grinstein ◽  
Varda Rotter
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Stromal Cells ◽  
Tumor Development ◽  
Tumor Stroma ◽  
P53 Mutation ◽  
Mutant P53 ◽  
Therapeutic Approaches ◽  
Recruitment Process ◽  
Cellular Components

Abstract A plethora of studies suggest that the non-transformed cellular and non-cellular components of the tumor, collectively known as the tumor microenvironment, have a significant impact on the tumorigenic process. It was suggested that the microenvironment, which initially restricts tumor development, is recruited by the tumor and maintains a crosstalk that further promotes cancer progression. Indeed, many of the molecules that participate in the tumor–stroma crosstalk have been characterized. However, the crucial factors that are responsible for the initiation of this crosstalk or the ‘recruitment’ process remain poorly understood. We propose that oncogenes themselves may influence the ‘recruitment’ of the stromal cells, while focusing on mutant p53. Apart from losing its tumor-suppressing properties, mutant p53 gains novel oncogenic functions, a phenomenon dubbed mutant p53 gain of function (GOF). Here, we discuss possible ways in which mutant p53 may modulate the microenvironment in order to promote tumorigenesis. We thus propose that mutant p53 may serve as a key player in the modulation of the tumor–stroma crosstalk in a way that benefits the tumor. Further elucidation of these ‘recruitment’ processes, dictated by mutant p53, may be utilized for tailoring personalized therapeutic approaches for patients with tumors that harbor p53 mutation.

scholarly journals The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

2020 ◽  
Vol 11 ◽  
Author(s):  
Shahid Hussain ◽  
Bo Peng ◽  
Mathew Cherian ◽  
Jonathan W. Song ◽  
Dinesh K. Ahirwar ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Tumor Development ◽  
Inflammatory Cells ◽  
Host Cells ◽  
Metastatic Niche ◽  
Cancer Pathogenesis ◽  
Cancer Metastases ◽  
Cellular Components

The intricate interplay between malignant cells and host cellular and non-cellular components play crucial role in different stages of tumor development, progression, and metastases. Tumor and stromal cells communicate to each other through receptors such as integrins and secretion of signaling molecules like growth factors, cytokines, chemokines and inflammatory mediators. Chemokines mediated signaling pathways have emerged as major mechanisms underlying multifaceted roles played by host cells during tumor progression. In response to tumor stimuli, host cells-derived chemokines further activates signaling cascades that support the ability of tumor cells to invade surrounding basement membrane and extra-cellular matrix. The host-derived chemokines act on endothelial cells to increase their permeability and facilitate tumor cells intravasation and extravasation. The tumor cells-host neutrophils interaction within the vasculature initiates chemokines driven recruitment of inflammatory cells that protects circulatory tumor cells from immune attack. Chemokines secreted by tumor cells and stromal immune and non-immune cells within the tumor microenvironment enter the circulation and are responsible for formation of a “pre-metastatic niche” like a “soil” in distant organs whereby circulating tumor cells “seed’ and colonize, leading to formation of metastatic foci. Given the importance of host derived chemokines in cancer progression and metastases several drugs like Mogamulizumab, Plerixafor, Repertaxin among others are part of ongoing clinical trial which target chemokines and their receptors against cancer pathogenesis. In this review, we focus on recent advances in understanding the complexity of chemokines network in tumor microenvironment, with an emphasis on chemokines secreted from host cells. We especially summarize the role of host-derived chemokines in different stages of metastases, including invasion, dissemination, migration into the vasculature, and seeding into the pre-metastatic niche. We finally provide a brief description of prospective drugs that target chemokines in different clinical trials against cancer.

scholarly journals Biological mechanisms linked to inflammation in cancer: Discovery of tumor microenvironment-related biomarkers and their clinical application in solid tumors

2020 ◽  
Vol 35 (1_suppl) ◽  
pp. 8-11 ◽  
Author(s):  
Paola Nisticò ◽  
Gennaro Ciliberto
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Tumor Development ◽  
Short Paper ◽  
Great Relevance ◽  
Cellular Components ◽  
The Relationship

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

scholarly journals Targeting the Tumor Microenvironment for Cancer Therapy

2013 ◽  
Vol 59 (1) ◽  
pp. 85-93 ◽  
Author(s):  
Nor Eddine Sounni ◽  
Agnès Noel
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Local Environment ◽  
Tumor Stroma ◽  
Host Cells ◽  
Stromal Compartment ◽  
Tumor Infiltrate ◽  
Cellular Components

BACKGROUND With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. CONTENT The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. SUMMARY A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix.

scholarly journals Cancer: a mirrored room between tumor bulk and tumor microenvironment

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Pablo Hernández-Camarero ◽  
Elena López-Ruiz ◽  
Juan Antonio Marchal ◽  
Macarena Perán
Keyword(s):  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Development ◽  
Cell Types ◽  
Molecular Signature ◽  
Therapeutic Approaches ◽  
Metastatic Niche ◽  
Systematic Analysis ◽  
Tumor Mass ◽  
Functional Transformations

AbstractIt has been well documented that the tumor microenvironment (TME) plays a key role in the promotion of drug resistance, the support of tumor progression, invasiveness, metastasis, and even the maintenance of a cancer stem-like phenotype. Here, we reviewed TME formation presenting it as a reflection of a tumor’s own organization during the different stages of tumor development. Interestingly, functionally different groups of stromal cells seem to have specific spatial distributions within the TME that change as the tumor evolves into advanced stage progression which correlates with the fact that cancer stem-like cells (CSCs) are located in the edges of solid tumor masses in advanced tumors.We also focus on the continuos feedback that is established between a tumor and its surroundings. The “talk” between tumor mass cells and TME stromal cells, marks the evolution of both interlocuting cell types. For instance, the metabolic and functional transformations that stromal cells undergo due to tumor corrupting activity.Moreover, the molecular basis of metastatic spread is also approached, making special emphasis on the site-specific pre-metastatic niche formation as another reflection of the primary tumor molecular signature.Finally, several therapeutic approaches targeting primary TME and pre-metastatic niche are suggested. For instance, a systematic analysis of the TME just adjacent to the tumor mass to establish the proportion of myofibroblasts-like cancer-associated fibroblasts (CAFs) which may in turn correspond to stemness and metastases-promotion. Or the implementation of “re-education” therapies consisting of switching tumor-supportive stromal cells into tumor-suppressive ones. In summary, to improve our clinical management of cancer, it is crucial to understand and learn how to manage the close interaction between TME and metastasis.

scholarly journals LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 195
Author(s):  
Francisca Dias ◽  
Cristina Almeida ◽  
Ana Luísa Teixeira ◽  
Mariana Morais ◽  
Rui Medeiros
Keyword(s):  
Colorectal Cancer ◽  
Amino Acid ◽  
Cancer Progression ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Amino Acid Transporters ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Colorectal Cancer Progression ◽  
Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

scholarly journals CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Alessandra Righetti ◽  
Matteo Giulietti ◽  
Berina Šabanović ◽  
Giulia Occhipinti ◽  
Giovanni Principato ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Stromal Cells ◽  
Tumor Invasion ◽  
Epithelial To Mesenchymal Transition ◽  
Current Knowledge ◽  
Tumor Development ◽  
Physiological Role ◽  
Mesenchymal Transition ◽  
Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

scholarly journals TLR4 signaling drives mesenchymal stromal cells commitment to promote tumor microenvironment transformation in multiple myeloma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Cesarina Giallongo ◽  
Daniele Tibullo ◽  
Giuseppina Camiolo ◽  
Nunziatina L. Parrinello ◽  
Alessandra Romano ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Immune Escape ◽  
In Vivo Model ◽  
Th2 Response ◽  
Tlr4 Signaling

Abstract Inflammation represents a key feature and hallmark of tumor microenvironment playing a major role in the interaction with mesenchymal stromal cells (MSC) in cancer progression. The aim of the present study was to investigate the crosstalk between MSCs and myeloma cells (MM) in the pro-inflammatory microenvironment promoting immune evasion and tumor growth. MSC were collected from patients with diagnosis of MGUS (n = 10), smoldering myeloma (n = 7), multiple myeloma at diagnosis (n = 16), relapse (n = 5) or refractory (n = 3), and from age-matched healthy controls (HC, n = 10) and cultured with peripheral blood mononucleated cells (PBMC) from healthy volunteer donors. Similarly to MM, we showed that MSC from smoldering multiple myeloma (SMM) patients activated neutrophils and conferred an immunosuppressive and pro-angiogenic phenotype. Furthermore, co-cultures of plasma cells (PC) and HC-MSC suggested that such activation is driven by MM cells through the switching into a pro-inflammatory phenotype mediated by toll-like receptor 4 (TLR4). These results were further confirmed using a zebrafish as an immunocompetent in vivo model, showing the role of MM–MSC in supporting PCs engraftment and Th2 response. Such effect was abolished following inhibition of TLR4 signaling in MM–MSC before co-injection with PC. Moreover, the addition of a TLR4 inhibitor in the co-culture of HC-MSC with MM cells prevented the activation of the pro-tumor activity in PC-educated MSC. In conclusion, our study provides evidence that TLR4 signaling plays a key role in MSC transformation by inducing a pro-tumor phenotype associated with a permissive microenvironment allowing immune escape and tumor growth.

scholarly journals Role of MSC in the Tumor Microenvironment

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2107 ◽  
Author(s):  
Ralf Hass
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Development ◽  
Tumor Stroma ◽  
Cell Types ◽  
Cellular Interactions ◽  
Cell Functions ◽  
Metastatic Behavior ◽  
Stem Cell Niches

The tumor microenvironment represents a dynamically composed matrix in which tissue-associated cancer cells are embedded together with a variety of further cell types to form a more or less separate organ-like structure. Constantly mutual interactions between cells of the tumor microenvironment promote continuous restructuring and growth in the tumor. A distinct organization of the tumor stroma also facilitates the formation of transient cancer stem cell niches, thereby contributing to progressive and dynamic tumor development. An important but heterogeneous mixture of cells that communicates among the cancer cells and the different tumor-associated cell types is represented by mesenchymal stroma-/stem-like cells (MSC). Following recruitment to tumor sites, MSC can change their functionalities, adapt to the tumor’s metabolism, undergo differentiation and synergize with cancer cells. Vice versa, cancer cells can alter therapeutic sensitivities and change metastatic behavior depending on the type and intensity of this MSC crosstalk. Thus, close cellular interactions between MSC and cancer cells can eventually promote cell fusion by forming new cancer hybrid cells. Consequently, newly acquired cancer cell functions or new hybrid cancer populations enlarge the plasticity of the tumor and counteract successful interventional strategies. The present review article highlights some important features of MSC within the tumor stroma.

Tumor-Host Interactions: A Far-Reaching Relationship

2010 ◽  
Vol 28 (26) ◽  
pp. 4022-4028 ◽  
Author(s):  
Sandra S. McAllister ◽  
Robert A. Weinberg
Keyword(s):  
Cancer Progression ◽  
Stromal Cells ◽  
Tumor Biology ◽  
Mesenchymal Cell ◽  
Tumor Stroma ◽  
Cell Types ◽  
Host Interactions ◽  
Recent Advances ◽  
Extracellular Matrix Components ◽  
Heterotypic Interactions

Carcinomas are composed of neoplastic epithelial cells, which form the heart of the tumor, as well as a variety of mesenchymal cell types and extracellular matrix components that comprise the tumor stroma, often termed its microenvironment. The normal counterparts of some stromal cells are thought to limit tumor growth, while tumor-associated stromal cells have been convincingly shown to actively promote tumor progression via complex heterotypic interactions with the nearby carcinoma cells. More recent advances have revealed that tumor-host interactions extend well beyond the local tissue microenvironment (ie, interactions between the neoplastic cells and the nearby stroma) and that tumors not only respond to, but actively perturb host organs at distant anatomic sites. This indicates that many aspects of tumor biology can only be explained by a detailed understanding of both local and systemic interactions, yet we currently have only a fragmentary understanding of both processes. In this review, we address the recent advances in our understanding of the contributions of local and systemic environments to cancer progression, the ability of tumors to actively perturb the host environment, and current therapeutic approaches that are designed to disrupt tumor-host relationships.

scholarly journals NKG2D signaling regulates IL-17A-producing γδT cells to promote cancer progression

2021 ◽  
Author(s):  
Sophie Curio ◽  
Sarah C Edwards ◽  
Toshiyasu Suzuki ◽  
Jenny McGovern ◽  
Chiara Triulzi ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Cell Activation ◽  
Tumor Development ◽  
Cell Receptor ◽  
Dependent Manner ◽  
Γδt Cells ◽  
Γδt Cell

γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance and homeostasis. γδT cell activation is mediated by the T cell receptor composed of γ and δ chains, as well as activating receptors for stress-induced ligands, such as NKG2D. Contrary to the well-established anti-tumor function of γδT cells, recent studies have shown that γδT cells can promote tumor development in certain contexts. However, the mechanisms leading to this disease-promoting role remain poorly understood. Here, we show that mice lacking γδT cells survive longer in a mouse model of intestinal cancer, further supporting their pro-tumoral role. In a surprising conceptual twist, we found that these pro-tumor γδT cells are regulated by NKG2D signaling, a receptor normally associated with cancer cell killing. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduces the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increases the frequency of γδT cells. Together, these data support the hypothesis that in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.

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