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

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.

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

The International Journal of Biological Markers ◽

10.1177/1724600820906155 ◽

2020 ◽

Vol 35 (1_suppl) ◽

pp. 8-11 ◽

Cited By ~ 3

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.

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Targeting the Tumor Microenvironment for Cancer Therapy

Clinical Chemistry ◽

10.1373/clinchem.2012.185363 ◽

2013 ◽

Vol 59 (1) ◽

pp. 85-93 ◽

Cited By ~ 191

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.

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

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjz071 ◽

2019 ◽

Vol 11 (7) ◽

pp. 600-604 ◽

Cited By ~ 6

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.

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The Roles of CD38 and CD157 in the Solid Tumor Microenvironment and Cancer Immunotherapy

Cells ◽

10.3390/cells9010026 ◽

2019 ◽

Vol 9 (1) ◽

pp. 26 ◽

Cited By ~ 2

Author(s):

Yu Jun Wo ◽

Adelia Shin Ping Gan ◽

Xinru Lim ◽

Isabel Shu Ying Tay ◽

Sherlly Lim ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Tumor Cells ◽

Cancer Progression ◽

Solid Tumor ◽

Immune Cells ◽

Tumor Development ◽

Cancer Prognosis ◽

Immune Resistance ◽

Tumor Types

The tumor microenvironment (TME) consists of extracellular matrix proteins, immune cells, vascular cells, lymphatics and fibroblasts. Under normal physiological conditions, tissue homeostasis protects against tumor development. However, under pathological conditions, interplay between the tumor and its microenvironment can promote tumor initiation, growth and metastasis. Immune cells within the TME have an important role in the formation, growth and metastasis of tumors, and in the responsiveness of these tumors to immunotherapy. Recent breakthroughs in the field of cancer immunotherapy have further highlighted the potential of targeting TME elements, including these immune cells, to improve the efficacy of cancer prognostics and immunotherapy. CD38 and CD157 are glycoproteins that contribute to the tumorigenic properties of the TME. For example, in the hypoxic TME, the enzymatic functions of CD38 result in an immunosuppressive environment. This leads to increased immune resistance in tumor cells and allows faster growth and proliferation rates. CD157 may also aid the production of an immunosuppressive TME, and confers increased malignancy to tumor cells through the promotion of tumor invasion and metastasis. An improved understanding of CD38 and CD157 in the TME, and how these glycoproteins affect cancer progression, will be useful to develop both cancer prognosis and treatment methods. This review aims to discuss the roles of CD38 and CD157 in the TME and cancer immunotherapy of a range of solid tumor types.

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A MicroRNA Component of the Neoplastic Microenvironment: Microregulators with Far-Reaching Impact

BioMed Research International ◽

10.1155/2013/762183 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Xiaolei Li ◽

Zhiqiang Wu ◽

Xiaobing Fu ◽

Weidong Han

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Tumor Development ◽

Related Gene ◽

Biological Mechanisms ◽

Aberrant Expression ◽

Small Noncoding Rnas ◽

Cancer Related Gene ◽

Microenvironmental Factors

The interplay between tumor cells and their microenvironment plays a pivotal role in tumor development and progression. Although a growing body of evidence has established the importance of the tumor microenvironment, an understanding of the crosstalk between its components and cancer cells remains elusive. The pathways triggered by microenvironmental factors could modulate cancer-related gene transcription, also affecting small noncoding RNAs, microRNAs, which have emerged as key posttranscriptional regulators of gene expression, directly involved in human cancers. Although microRNAs regulate most biological mechanisms, their role in the tumor microenvironment has only recently become the focus of intense research. In this paper, we focus on the intertwined connection between the tumor microenvironment and aberrant expression of microRNAs involved in carcinogenesis. We also discuss the emerging roles of microRNAs in the tumor microenvironment as it relates to cancer progression. We conclude that microRNAs are critical for our understanding of the development of cancer, and that targeting microRNA signaling pathways in the microenvironment as well as in tumor cells opens new therapeutic avenues to the global control of cancer.

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Tumor Microenvironment and Immunotherapy Response in Head and Neck Cancer

Cancers ◽

10.3390/cancers12113377 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3377

Author(s):

Panagiota Economopoulou ◽

Ioannis Kotsantis ◽

Amanda Psyrri

Keyword(s):

Head And Neck Cancer ◽

Tumor Microenvironment ◽

Head And Neck ◽

Neck Cancer ◽

Immune Escape ◽

Treatment Resistance ◽

Inflammatory Cells ◽

Tumor Evolution ◽

Complex Interactions ◽

Cellular Components

The tumor microenvironment (TME) encompasses cellular and non-cellular components which play an important role in tumor evolution, invasion, and metastasis. A complicated interplay between tumor cells and adjacent TME cells, such as stromal cells, immune cells, inflammatory cells, and cytokines, leads to severe immunosuppression and the proliferation of cancer cells in several solid tumors. An immunosuppressive TME has a significant impact on treatment resistance and may guide response to immunotherapy. In head and neck cancer (HNC), immunotherapeutic drugs have been incorporated in everyday clinical practice. However, despite an exceptional rate of durable responses, only a low percentage of patients respond. In this review, we will focus on the complex interactions occurring in this dynamic system, the TME, which orchestrate key events that lead to tumor progression, immune escape, and resistance. Furthermore, we will summarize current clinical trials that depict the TME as a potential therapeutic target for improved patient selection.

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Semaphorin Signaling in Cancer-Associated Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms20020377 ◽

2019 ◽

Vol 20 (2) ◽

pp. 377 ◽

Cited By ~ 12

Author(s):

Giulia Franzolin ◽

Luca Tamagnone

Keyword(s):

Immune Response ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Disease Progression ◽

Tumor Cells ◽

Cross Talk ◽

Immune Cells ◽

Major Element ◽

Inflammatory Cells ◽

Anti Cancer

The inflammatory and immune response elicited by the growth of cancer cells is a major element conditioning the tumor microenvironment, impinging on disease progression and patients’ prognosis. Semaphorin receptors are widely expressed in inflammatory cells, and their ligands are provided by tumor cells, featuring an intense signaling cross-talk at local and systemic levels. Moreover, diverse semaphorins control both cells of the innate and the antigen-specific immunity. Notably, semaphorin signals acting as inhibitors of anti-cancer immune response are often dysregulated in human tumors, and may represent potential therapeutic targets. In this mini-review, we provide a survey of the best known semaphorin regulators of inflammatory and immune cells, and discuss their functional impact in the tumor microenvironment.

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Hypoxia-inducible factor (HIF): fuel for cancer progression

Current Molecular Pharmacology ◽

10.2174/1874467214666210120154929 ◽

2021 ◽

Vol 14 ◽

Author(s):

Saurabh Satija ◽

Harpreet Kaur ◽

Murtaza M. Tambuwala ◽

Prabal Sharma ◽

Manish Vyas ◽

...

Keyword(s):

Biological Sciences ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Oxygen Deficiency ◽

Hypoxia Inducible Factor ◽

Transcription Factor Activation ◽

Underlying Mechanisms ◽

Adaptive Reactions

Hypoxia is an integral part of tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mchanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

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Blood Vessels and Peripheral Nerves as Key Players in Cancer Progression and Therapy Resistance

Cancers ◽

10.3390/cancers13174471 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4471

Author(s):

Niccolò Roda ◽

Giada Blandano ◽

Pier Giuseppe Pelicci

Keyword(s):

Cancer Cells ◽

Blood Vessels ◽

Cancer Progression ◽

Peripheral Nerves ◽

Tumor Development ◽

Therapy Resistance ◽

Tumor Mass ◽

Cancer Pathogenesis ◽

Initial Results ◽

Metastatic Spreading

Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments.

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

10.1101/2021.08.26.457761 ◽

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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