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Cancers
Special Issues
TAM family receptors in cancer biology and therapeutic resistance
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TAM family receptors in cancer biology and therapeutic resistance

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 August 2016) | Viewed by 51423

Special Issue Editors

Prof. Dr. Deric L. Wheeler

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Guest Editor
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53703, USA
Interests: TAM family receptors; therapeutic resistance; antibody based therapy; Receptor Tyrosine Kinases
Dr. Toni M. Brand

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Guest Editor
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 97104, USA
Interests: Head and Neck cancer; PI3K signaling; cancer therapeutics

Special Issue Information

Dear Colleagues,

Receptor tyrosine kinases (RTKs) are cell surface receptors that have the capacity to catalyze the phosphorylation of tyrosine residues on target proteins. Thus, RTKs play essential roles in activating the cell signaling pathways that control a diverse array of cellular functions, including cellular proliferation, migration, survival, angiogenesis, and metabolism. The TAM family of RTKs consists of three receptors, Axl, Tyro, and MerTK. All TAM family receptors have an extracellular ligand binding domain, a single-pass transmembrane domain, an intracellular kinase domain, and a tyrosine containing C-terminal tail. Upon binding to cognate ligands, Gas6 or Protein S, TAM family receptors can homo- or hetero- dimerize, resulting in kinase domain activation and C-terminal tail phosphorylation. The activation of TAM receptors results in signaling down several growth promoting pathways, such as the phosphatidylinositol-3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) pathways.

Over the last ten years, TAM family receptors and their ligands have been implicated in the development and progression of several human cancers. These studies have reported TAM receptors to be overexpressed or hyper-activated in many tumor types, correlating with poor patient prognosis. Most recently, the Axl receptor has been found to mediate resistance to several different cancer therapies, including chemotherapy, radiation, anti-epidermal growth factor receptor (EGFR) therapy, and PI3K inhibitors. Furthermore, TAM family receptors are essential regulators of epithelial-mesenchymal transition (EMT), which results in therapeutic resistance, metastasis, and immune cell suppression. These data demonstrate an important role for TAM receptors in cancer biology and therapeutic response.

This Special Issue will cover subjects related to TAM family receptors in cancer biology and response to therapeutic agents. Thus, a broad focus, ranging from the basic biology of TAM family receptors in tumor cells to the preclinical and clinical evaluation of TAM family inhibitors for the treatment of cancer patients, will be included. Collectively, this issue will advance our knowledge of TAM family receptors in cancer, and will insight new research focused on this family of RTKs in the future.

Prof. Dr. Deric L. Wheeler
Dr. Toni M. Brand
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • therapy
  • receptor tyrosine kinases
  • TAM family receptors
  • Axl
  • cell signaling
  • drug resistance

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Published Papers (4 papers)

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Review

1442 KiB  
Review
Ligand Activation of TAM Family Receptors-Implications for Tumor Biology and Therapeutic Response
by Viralkumar Davra, Stanley G. Kimani, David Calianese and Raymond B. Birge
Cancers 2016, 8(12), 107; https://doi.org/10.3390/cancers8120107 - 29 Nov 2016
Cited by 56 | Viewed by 10623
Abstract
The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor [...] Read more.
The TAM family of receptors (i.e., Tyro3, Axl, and Mertk), and their ligands Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) contribute to several oncogenic processes, such as cell survival, invasion, migration, chemo-resistance, and metastasis, whereby expression often correlates with poor clinical outcomes. In recent years, there has been great interest in the study of TAM receptors in cancer, stemming both from their roles as oncogenic signaling receptors, as well as their roles in tumor immunology. As a result, several classes of TAM inhibitors that include small molecule tyrosine kinase inhibitors, monoclonal antibodies, decoy receptors, as well as novel strategies to target TAM ligands are being developed. This paper will review the biology of TAM receptors and their ligands with a focus on cancer, as well as evidence-based data for the continued pursuit of TAM/Gas6 inhibitors in clinical practice. Full article
(This article belongs to the Special Issue TAM family receptors in cancer biology and therapeutic resistance)
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1309 KiB  
Review
The Receptor Tyrosine Kinase AXL in Cancer Progression
by Erinn B. Rankin and Amato J. Giaccia
Cancers 2016, 8(11), 103; https://doi.org/10.3390/cancers8110103 - 9 Nov 2016
Cited by 127 | Viewed by 14746
Abstract
The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed [...] Read more.
The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy. Full article
(This article belongs to the Special Issue TAM family receptors in cancer biology and therapeutic resistance)
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1060 KiB  
Review
Targeting the TAM Receptors in Leukemia
by Madeline G. Huey, Katherine A. Minson, H. Shelton Earp, Deborah DeRyckere and Douglas K. Graham
Cancers 2016, 8(11), 101; https://doi.org/10.3390/cancers8110101 - 8 Nov 2016
Cited by 30 | Viewed by 11652
Abstract
Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell [...] Read more.
Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition. Full article
(This article belongs to the Special Issue TAM family receptors in cancer biology and therapeutic resistance)
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1494 KiB  
Review
The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy
by Magdalena Paolino and Josef M. Penninger
Cancers 2016, 8(10), 97; https://doi.org/10.3390/cancers8100097 - 21 Oct 2016
Cited by 92 | Viewed by 13281
Abstract
The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as [...] Read more.
The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy. Full article
(This article belongs to the Special Issue TAM family receptors in cancer biology and therapeutic resistance)
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