The role of lipids in cancer progression and metastasis.

Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune-associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mco2.27

Lipid metabolism in cancer progression and therapeutic strategies

STAT proteins in cancer: orchestration of metabolism

Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, inexpensive, and less toxic sources of chemotherapeutic agents. Additionally, they have multiple mechanisms of action to inhibit various targets involved in the development of drug resistance. In this review, we have summarized the basic research and clinical applications of natural products as possible inhibitors for drug resistance in cancer. The molecular targets and the mechanisms of action of each natural product are also explained. Diverse drug resistance biomarkers were sensitive to natural products. P-glycoprotein and breast cancer resistance protein can be targeted by a large number of natural products. On the other hand, protein kinase C and topoisomerases were less sensitive to most of the studied natural products. The studies discussed in this review will provide a solid ground for scientists to explore the possible use of natural products in combination anticancer therapies to overcome drug resistance by targeting multiple drug resistance mechanisms.

Targeting Drug Chemo-Resistance in Cancer Using Natural Products

Abstract Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of cancer cells. The correlation between TME and CSCs remains an enigma in understanding the events of metastasis and therapy resistance in cancer biology. Recent evidence suggests that TME dictates the CSCs maintenance to arbitrate cancer progression and metastasis. The immune, inflammatory, endothelial, adipocyte, and fibroblast cells in the TME release growth factors, cytokines, chemokines, microRNAs, and exosomes that provide cues for the gain and maintenance of CSC features. These intricate cross-talks are fueled to evolve into aggressive, invasive, migratory phenotypes for cancer development. In this review, we have abridged the recent developments in the role of the TME factors in CSC maintenance and how these events influence the transition of tumor progression to further translate into metastasis and therapy resistance in cancer. 

/pdf/tumor-microenvironment-enriches-the-stemness-features-the-136hczx2.pdf

Tumor microenvironment enriches the stemness features: the architectural event of therapy resistance and metastasis

Adipose tissue has been considered as a crucial source of certain pro-inflammatory cytokines; conversely, these pro-inflammatory cytokines are involved in regulating the proliferation and apoptosis of adipocytes, promoting lipolysis, inhibiting lipid synthesis and decreasing blood lipids, etc. In recent decades, extensive studies have indicated that pro-inflammatory cytokines play important roles in the development of lipid metabolism of metabolic diseases, including obesity, atherosclerosis, steatohepatitis and hyperlipoproteinemia. However, the involved pro-inflammatory cytokines types and the underlying mechanisms remain largely unknown. The "re-discovery" of cancer as a metabolic disorder largely occurred in the last five years. Although pro-inflammatory cytokines have been intensively investigated in cancer research, there are very few studies about the roles of pro-inflammatory cytokines in the lipid metabolism of cancer. In the current review, we provide an overview of the progress that has been made in the roles of different pro-inflammatory cytokines in lipid metabolism of metabolic diseases including cancer.

The role of pro-inflammatory cytokines in lipid metabolism of metabolic diseases.

IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells.

Pro-inflammatory cytokines are crucial mediators of cancer development, representing potential targets for cancer therapy. The molecular mechanism of a vital pro-inflammatory cytokine, IL-17A, in cancer progression and its potential use in therapy through influencing fatty acid (FA) metabolism, especially FA uptake of cancer cells, remains unknown. In the present study, we used IL-17A and ovarian cancer (OvCa), a representative of both obesity-related and inflammation-related cancers, to explore the interactions among IL-17A, cancer cells and adipocytes (which can provide FAs). We found that in the presence of palmitic acid (PA), IL-17A could directly increase the cellular uptake of PA, leading to the proliferation of OvCa cells via the IL-17A/IL-17RA/p-STAT3/FABP4 axis rather than via CD36. Moreover, in vivo experiments using an orthotopic implantation model in IL-17A-deficient mice demonstrated that endogenous IL-17A could fuel OvCa growth and metastasis with increased expression of FABP4 and p-STAT3. Furthermore, analysis of clinical specimens supported the above findings. Our data not only provide useful insights into the clinical intervention of the growth and metastasis of the tumors (such as OvCa) that are prone to growth and metastasis in an adipocyte-rich microenvironment (ARM) but also provides new insights into the roles of IL-17A in tumor progression and immunomodulatory therapy of OvCa.

IL-17A promotes fatty acid uptake through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to fuel ovarian cancer growth in an adipocyte-rich microenvironment

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The role of pro-inflammatory cytokines in lipid metabolism of metabolic diseases.

IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells.

IL-17A promotes fatty acid uptake through the IL-17A/IL-17RA/p-STAT3/FABP4 axis to fuel ovarian cancer growth in an adipocyte-rich microenvironment