Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell ...metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.
The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates ...tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.
Increasing chemotherapy delivery to tumors, while enhancing drug uptake and reducing side effects, is a primary goal of cancer research. In mouse and human cancer models in vivo, we show that ...coadministration of low-dose Cilengitide and Verapamil increases tumor angiogenesis, leakiness, blood flow, and Gemcitabine delivery. This approach reduces tumor growth, metastasis, and minimizes side effects while extending survival. At a molecular level, this strategy alters Gemcitabine transporter and metabolizing enzyme expression levels, enhancing the potency of Gemcitabine within tumor cells in vivo and in vitro. Thus, the dual action of low-dose Cilengitide, in vessels and tumor cells, improves chemotherapy efficacy. Overall, our data demonstrate that vascular promotion therapy is a means to improve cancer treatment.
•Vascular promotion is distinct from antiangiogenesis and vascular normalization•Vascular promotion enhances tumor angiogenesis, flow, leakiness, and drug delivery•Vascular promotion reduces tumor growth and metastasis while extending survival•Low-dose Cilengitide enhances Gemcitabine uptake and metabolism within tumor cells
Wong et al. demonstrates the efficacy of vascular promotion therapy, which is distinct from antiangiogenesis and vascular normalization. Coadministration of low-dose cilengitide and verapamil enhances tumor angiogenesis and gemcitabine delivery, resulting in reduced tumor growth and metastasis.
Highlights • Targeting the ectodomain of αvβ3 integrin can control tumour blood vessel development. • Facing the problems of targeting the integrin ectodomain. • Thinking about integrin endocytosis ...and targeting cytotail adhesome interactions.
Chemoresistance is a serious limitation of cancer treatment. Until recently, almost all the work done to study this limitation has been restricted to tumour cells. Here we identify a novel molecular ...mechanism by which endothelial cells regulate chemosensitivity. We establish that specific targeting of focal adhesion kinase (FAK; also known as PTK2) in endothelial cells is sufficient to induce tumour-cell sensitization to DNA-damaging therapies and thus inhibit tumour growth in mice. The clinical relevance of this work is supported by our observations that low blood vessel FAK expression is associated with complete remission in human lymphoma. Our study shows that deletion of FAK in endothelial cells has no apparent effect on blood vessel function per se, but induces increased apoptosis and decreased proliferation within perivascular tumour-cell compartments of doxorubicin- and radiotherapy-treated mice. Mechanistically, we demonstrate that endothelial-cell FAK is required for DNA-damage-induced NF-κB activation in vivo and in vitro, and the production of cytokines from endothelial cells. Moreover, loss of endothelial-cell FAK reduces DNA-damage-induced cytokine production, thus enhancing chemosensitization of tumour cells to DNA-damaging therapies in vitro and in vivo. Overall, our data identify endothelial-cell FAK as a regulator of tumour chemosensitivity. Furthermore, we anticipate that this proof-of-principle data will be a starting point for the development of new possible strategies to regulate chemosensitization by targeting endothelial-cell FAK specifically.
Systems Biology in Cancer Research and Drug Discovery provides a unique collection of chapters, by world-class researchers, describing the use of integrated systems biology and network modeling in ...the cancer field where traditional tools have failed to deliver expected promise. This book touches four applications/aspects of systems biology (i) in understanding aberrant signaling in cancer (ii) in identifying biomarkers and prognostic markers especially focused on angiogenesis pathways (iii) in unwinding microRNAs complexity and (iv) in anticancer drug discovery and in clinical trial design. This book reviews the state-of-the-art knowledge and touches upon cutting edge newer and improved applications especially in the area of network modeling. It is aimed at an audience ranging from students, academics, basic researcher and clinicians in cancer research. This book is expected to benefit the field of translational cancer medicine by bridging the gap between basic researchers, computational biologists and clinicians who have one ultimate goal and that is to defeat cancer.
Pancreatic cancer is an aggressive and highly lethal disease, with a reported 5-year survival of ∼5 %. It comprises the fourth most common cause of malignancy-related death in Western countries and ...the annual death rate due to this disease approximates its annual incidence rate, which is estimated to be ∼10 cases per 100,000 population. Although there have been some advancements in surgical techniques and adjuvant therapeutic regimens, the survival has not substantially improved in the past 30 years. Pancreatic cancer is characterized by late diagnosis, aggressive local invasion, early systemic dissemination and resistance to chemo- and radiotherapy. Therefore, a better understanding of cellular and molecular mechanisms governing the resistant phenotype of this devastating disease is urgently needed. Systems biology has emerged as one of the most promising approaches to understand the complexities of tumor-microenvironment interplay on a quantitative multi-scale level, i.e. by incorporating genomics, transcriptomics, proteomics, epigenomics and functional genomics studies. Integrative analysis of these data aims to dissect inter- and intracellular networks critically contributing to tumor progression and therapy resistance.
Passive antibody therapy has been used to immunize vulnerable people against infectious agents. In this study, we aim to investigate the efficacy of convalescent plasma (CP) in the treatment of ...severe and critically ill patients diagnosed with COVID-19.
The data of severe or critically ill COVID-19 patients who received anti-SARS-CoV-2 antibody-containing CP along with the antiviral treatment (n = 888) and an age-gender, comorbidity, and other COVID-19 treatments matched severe or critically ill COVID-19 patients at 1:1 ratio (n = 888) were analyzed retrospectively.
Duration in the intensive care unit (ICU), the rate of mechanical ventilation (MV) support and vasopressor support were lower in CP group compared with the control group (p = 0.001, p = 0.02, p = 0.001, respectively). The case fatality rate (CFR) was 24.7 % in the CP group, and it was 27.7 % in the control group. Administration of CP 20 days after the COVID-19 diagnosis or COVID-19 related symptoms were associated with a higher rate of MV support compared with the first 3 interval groups (≤5 days, 6−10 days, 11−15 days) (p=0.001).
CP therapy seems to be effective for a better course of COVID-19 in severe and critically ill patients.
Diverticular disease of the colon is a pathology that arises from outward ballooning of the mucosa due to some weakness in the muscle layer. Diverticular disease may range from symptomatic ...uncomplicated diverticular disease to symptomatic disease with complications, such as acute diverticulitis or diverticular bleeding. Acute colonic diverticulitis occurs in about 10- 25% of patients.
In this study, 134 patients who were admitted to our emergency clinic with complaints of abdominal pain between 2016-2019 and hospitalized with the diagnosis of acute diverticulitis were included. Patients' sex, age, presence of additional disease, increase in leukocyte and C-reactive protein (CRP), localization of diverticulitis, Hinchey classification, mean length of hospital stay and treatment were evaluated. The effects of these parameters on complications and recurrence were statistically analyzed.
The length of hospital stay was statistically significantly associated positively with the Hinchey classification (p<0.001). While 18 patients who were medically treated developed recurrence later, and this rate was statistically significant (p<0.001). When one of the factors, localization, which may play a role in the severity of the disease and recurrence are examined, was evaluated concerning its results in our study, we found that rectosigmoid location is an important factor for recurrence. We found that the localization in the colon and the severity of the disease were effective in the prognosis of acute diverticulitis.
We believe that localization and the severity of the disease should be taken into consideration when planning surgery in these patients.
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