https://www.cell.com/cell-metabolism/pdf/S1550-4131(15)00621-X.pdf

The Emerging Hallmarks of Cancer Metabolism

The Warburg Effect: How Does it Benefit Cancer Cells?

Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

Fundamentals of cancer metabolism

Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific T cells be generated, but also that these T cells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.

http://science.sciencemag.org/content/sci/348/6230/74.full.pdf

T cell exclusion, immune privilege, and the tumor microenvironment

https://www.cell.com/trends/immunology/pdf/S1471-4906(16)00005-3.pdf

The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment.

Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1α (HIF1α). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.

/pdf/functional-polarization-of-tumour-associated-macrophages-by-56kr8jsez3.pdf

Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

Surgery is the only potentially curative treatment for localized soft tissue sarcomas. However, for sarcomas arising in the retroperitoneum, locoregional recurrence rates are 35-59% despite resection. Doxorubicin (DOX) is the standard first-line systemic chemotherapy for advanced soft tissue sarcoma, yet its intravenous administration yields limited clinical efficacy and results in dose-limiting cardiotoxicity. We report the fabrication and optimization of a novel electrospun poly(caprolactone) (PCL) surgical mesh coated with layers of a hydrophobic polymer (poly(glycerol monostearate-co-caprolactone), PGC-C18), which delivers DOX directly to the operative bed following sarcoma resection. In xenograft models of liposarcoma and chondrosarcoma, doxorubicin-loaded meshes (DoM) increased overall survival four-fold compared to systemically administered DOX and prevented local recurrence in all but one animal. Importantly, mice implanted with DoMs exhibited preserved cardiac function, while mice receiving an equivalent dose systemically displayed a 23% decrease from baseline in both cardiac output and ejection fraction 20-days post administration. Collectively, this work demonstrates a feasible therapeutic approach to simultaneously prevent post-surgical tumor recurrence and minimize cardiotoxicity in soft tissue sarcoma.

Doxorubicin-Loaded Polymeric Meshes Prevent Local Recurrence After Sarcoma Resection While Avoiding Cardiotoxicity.

Long-Term Durability of Valve Sparing Root Replacement in Patients with and without Connective Tissue Disease.

ObjectiveThe 2 most acceptable techniques for reimplantation of the supra-aortic vessels in total arch replacement include the branched graft technique (debranching) or en bloc technique (island). We aim to review our experience with total arch replacement and report short- and long-term outcomes from a high-volume center dedicated to surgery for the thoracic aorta.MethodsThe aortic surgery database was queried to identify all consecutive patients undergoing total arch replacement between 1997 and 2022. Of the 426 patients who underwent total arch replacement, 303 (71%) received the island technique and 123 (29%) received the debranching approach. Operative and long-term outcomes were compared using multivariable models.ResultsThe debranching group was younger (64 ± 14 years vs 69 ± 12 years, P = .001), had undergone more previous cardiac operations (54.5% vs 27.4%, P < .001), and had more connective tissue disorder (20.3% vs 4.6%, P < .001). The debranching approach was associated with longer total circulatory arrest time (47 ± 15 minutes vs 37 ± 10 minutes, P < .001) and cardiac ischemic time (116 ± 41 minutes vs 100 ± 37 minutes, P < .001). More patients in the debranching group received blood products intraoperatively or postoperatively (56.1% vs 42.9%, P = .018). All other early outcomes did not differ between groups. Overall operative mortality was 1.4% (2.4% vs 1%, P = .486); the incidence of major postoperative complications was 6.3% (5.7% vs 6.6%, P = .897). Ten-year survival was 80% (78% vs 80.9%, log-rank P = .356). Multivariable Cox regression analysis demonstrated that neither surgical approach was associated with survival advantage (hazard ratio, 1.18; 0.73-1.89; P = .495).ConclusionsDebranching requires a longer operative time, with similar early and long-term outcomes. Preoperative comorbidity, not surgical technique, predicts major adverse events and long-term survival. 

/pdf/short-and-long-term-results-of-total-arch-replacement-2xypxd4j.pdf

Ngoc Quynh Chu

Papers

Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

Doxorubicin-Loaded Polymeric Meshes Prevent Local Recurrence After Sarcoma Resection While Avoiding Cardiotoxicity.

Long-Term Durability of Valve Sparing Root Replacement in Patients with and without Connective Tissue Disease.

Short- and Long-Term Results of Total Arch Replacement: Comparison Between Island and Debranching Techniques