TGF-β Sustains Tumor Progression through Biochemical and Mechanical Signal Transduction

Abstract

Transforming growth factor β (TGF-β) signaling transduces immunosuppressive biochemical and mechanical signals in the tumor microenvironment. In addition to canonical SMAD transcription factor signaling, TGF-β can promote tumor growth and survival by inhibiting proinflammatory signaling and extracellular matrix (ECM) remodeling. In this article, we review how TGF-β activated kinase 1 (TAK1) activation lies at the intersection of proinflammatory signaling by immune receptors and anti-inflammatory signaling by TGF-β receptors. Additionally, we discuss the role of TGF-β in the mechanobiology of cancer. Understanding how TGF-β dampens proinflammatory responses and induces pro-survival mechanical signals throughout cancer development is critical for designing therapeutics that inhibit tumor progression while bolstering the immune response.

Cannabinoids in the Pathophysiology of Skin Inflammation

“…However, the tumor microenvironment includes an inflammatory component, consisting of leukocytes, cytokines, and various signaling and transcription factors, that aid cancer survival, tumor development, metastasis, and therapy resistance [159]. Among these components, TGF-β can cause immunosuppression and promote tumor growth and survival, TNF-α is involved in cellular transformation, survival, and proliferation, while MMPs can favor tumor invasion through epithelial-mesenchymal transition in many cancers; all these molecules are found in the intersecting pathways of inflammation and carcinogenesis, and cannabinoids can regulate their expression [140,[160][161][162][163][164][165][166]. These common anti-inflammatory and anti-carcinogenic effects of cannabinoids make them excellent candidates for cancer treatment, as they act as the immunomodulatory substances that influence cell signaling in the tumor microenvironment.…”

The Role of TGFβ in Clinical Cancer Response

“…Once TGFβR serine/threonine kinases are activated, several signal transduction cascades are set in motion. These include biochemical signal transduction cascades involving receptor-regulated SMAD transcription factors, Ras-MAPK modulation, or TGFβ activated kinase 1 (TAK1), as well as mechanical signal transduction mechanisms mediated by latency-associated peptide (LAP) or latent TGFβ binding proteins (LTBPs) in the extracellular matrix [8].…”

“…In addition to its biochemically mediated signaling networks, TGFβ cascades can proceed via mechanical transduction pathways in which extracellular matrix components inhibit inflammation and promote cancer cell proliferation by way of mechanical forces applied to adhesion receptors on the cell surface [8]. Integrins physically link cytoskeletal proteins to extracellular components of the tumor microenvironment with TGFβ increasing β1 integrin presentation on the surface of cancer cells [17].…”

The topology of vitronectin: A complementary feature for neuroblastoma risk classification based on computer‐aided detection

“…Image analysis landscape has enormous potential to improve the quality of histological image interpretation, supporting without overruling pathologists in decision‐making . In the oncology field, a plethora of computational tools is being designed to capture medical information with the help and supervision of a variety of professionals such as pathologists, biologists or physicists . Morphometric analysis has often been used as a first approach, successfully highlighting new prognostic indicators .…”

“…4,5 In the oncology field, a plethora of computational tools is being designed to capture medical information with the help and supervision of a variety of professionals such as pathologists, biologists or physicists. [6][7][8] Morphometric analysis has often been used as a first approach, successfully highlighting new prognostic indicators. [9][10][11] However, more sophisticated techniques are needed to model highly complicated diseases like cancer.…”