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Introduction to Cancer, Conventional Therapies, and Bionano-Based Advanced Anticancer Strategies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Cancer associated fibroblasts (CAFs) have been shown to either promote the growth, spread, and survival of tumors through improvement in functionality or to retard tumorigenesis via unknown mechanisms [83]. At an early stage of tumor development, CAFs can mediate a tumor-enhancing inflammation derived by interleukin-1β [84].
Synthetic Compounds vs. Phytochemicals for the Treatment of Human Cutaneous Malignant Melanoma
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Jacqueline Maphutha, Namrita Lall
The tumor microenvironment is made up of cancer-associated fibroblasts, tumor associated macrophages, adipocytes, endothelial cells, immune cells and the extracellular matrix (Franco et al., 2020). PI3K inhibitors are largely used to target cancer cells specifically those that trigger apoptosis; however, the mechanism is largely affected by the development of resistance. Okkenhaug, Graupera, and Vanhaesebroeck (2016) suggested that isoform-selective PI3K inhibitors administered for a short period of time, i.e. three days, could enhance the functioning of blood vessels that supply nutrients and oxygen to the tumors. Improving the function of blood vessels through the downregulation of vascular endothelial growth factor (VEGF) enables effective drug delivery (chemotherapeutics, immunotherapy and targeted therapy) (Okkenhaug, Graupera, and Vanhaesebroeck, 2016).
Tumor Microenvironment, Therapeutic Resistance, and Personalized Medicine
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
In solid tissues, fibroblasts constitute the structural framework and maintain physiological homeostasis as a predominant mesenchymal lineage. However, cancer-associated fibroblasts (CAFs) are functionally distinct from their normal counterparts and frequently demonstrate pathological relevance. In the microenvironment milieu, normal fibroblasts can be transformed into CAFs once stimulated by local tissue-derived proteins such as fibroblast growth factor (FGF), monocyte chemotactic protein 1 (MCP-1), platelet-derived growth factor (PDGF), tissue inhibitor of metalloproteinase 1 (TIMP-1) and tumor transforming growth factor β (TGF-β) [6, 7]. Despite the tumor-suppressive capacity in certain malignancies including pancreatic ductal adenocarcinoma (PDA), CAFs exhibit aggressive proliferation, augmented ECM deposition, enhanced cytokine synthesis/secretion (for instance, fibroblast growth factor 7 (FGF7); hepatocyte growth factor (HGF); interleukin 6 (IL-6); PDGF; stromal cell-derived factor 1, (SDF-1); and vascular endothelial growth factor (VEGF)), a unique stromal phenotype characterized with a chemoresistance-triggering secretome that can be abolished upon mTOR/4E-BP1 translation pathway blockade [4, 8].
A PDGFRB- and CD40-targeting bispecific AffiMab induces stroma-targeted immune cell activation
Published in mAbs, 2023
Alessandro Mega, Aman Mebrahtu, Gustav Aniander, Eva Ryer, Annette Sköld, Anna Sandegren, Eva Backström Rydin, Johan Rockberg, Arne Östman, Fredrik Y. Frejd
Immunotherapy has recently emerged as a promising approach for the treatment of several types of cancer. One emerging target for immunotherapy is CD40, a member of the TNF (tumor necrosis factor) receptor superfamily characteristically expressed by antigen-presenting cells (APC) such as dendritic cells (DCs), B cells and macrophages.1 Cells of the tumor microenvironment such as cancer associated fibroblasts (CAFs) favor immune escape and an immune suppressive milieu in cancer.2 Activation of CD40 on APC has the potential to revert immune suppression by activating both innate and adaptive immune response against cancer.3 CD40-expressing cells are a major component of tumor-infiltrating leukocytes.4 The activation of CD40 is governed by the buildup of receptor superclusters to elicit downstream signaling, wherein the receptor’s natural agonistic ligand confers signaling in its trimeric form. An important characteristic of CD40 agonism is that receptor clustering on the membrane of CD40 expressing cells is the key to activation of the downstream signaling.3
Locked and loaded: engineering and arming oncolytic adenoviruses to enhance anti-tumor immune responses
Published in Expert Opinion on Biological Therapy, 2022
The aberrant vasculature in some solid tumors causes high tumor interstitial fluid pressure (IFP) that can compress lymphatics and vessels reducing the ability of immune cells to enter tumors [100,101]. Tumor cells can also recruit non-cancerous stroma cells to form solid physical barriers that prevent immune cells from penetrating beyond blood vessels and lymphatics [102]. Cancer cells recruit cancer-associated fibroblasts (CAFs). These are a particular problem as they secrete extracellular matrix (ECM) materials, including collagen and fibronectin to form a tight extracellular physical barrier that prevents immune cells from migrating within solid tumors [102]. The added ECM also induces mechanical stress in the tumor to induce the production of transforming growth factor-beta (TGF-β) from these stroma cells. TGF-β secretion further increases collagen production by CAFs and inhibits T cell infiltration [101]. Beyond these physical barriers to immune cell infiltration, tumors frequently lack the expression of chemokines and proper adhesion molecules for T cells to home to the tumor and infiltrate into its core [103].
Safety of ramucirumab treatment in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein
Published in Expert Opinion on Drug Safety, 2022
VEGF facilitates pro-tumor neovascular network formation and thereby promotes cancer progression [17]. Among all the VEGF signaling pathways, VEGF receptor-2 (VEGFR-2) plays a pivotal role in vascular proliferation and permeability; therefore, selective inhibition of VEGFR-2 confers antineoplastic activity in HCC [18]. Ramucirumab (IMC-1121B or LY3009806) is a highly efficacious humanized IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2 and prevents activation and downstream signaling of VEGF [19]. It increases vascular permeability and proliferation and shows antibody-dependent cytotoxicity against tumor cells [20]. Recent studies have reported that VEGF promotes immunosuppression and attenuates the antitumor immune response via accumulation of regulatory T cells and myeloid-derived tumor suppressor cells 21,22]. VEGF-induced recruitment of tumor-associated macrophages and polarization to the M2 phenotype suppresses proliferation of tumor-infiltrating lymphocytes 21,23]. Effector T and natural killer cells are inactivated by inhibitory cytokines and immune checkpoint signals [24]. Cancer-associated fibroblasts also regulate VEGF in an immunosuppressive microenvironment to create a tumor-promoting niche [25]. Therefore, VEGF inhibitors such as ramucirumab, which stimulate vessel normalization and reprogramming of the immune microenvironment are associated with antineoplastic activity and improve drug delivery and act synergistically with other immunotherapeutic agents [26,27]. Figure 1 shows the diagrammatic representation of VEGF and its oncogenic and immunosuppressive actions.