Current perspectives between metabolic syndrome and cancer

Metabolic syndrome is a cluster of risk factors that lead to cardiovascular morbidity and mortality. Recent studies linked metabolic syndrome and several types of cancer. Although metabolic syndrome may not necessarily cause cancer, it is linked to poorer cancer outcomes including increased risk of recurrence and overall mortality. This review tends to discuss the major biological and physiological alterations involved in the increase of incidence and mortality of cancer patients affected by metabolic syndrome. We focus on metabolic syndrome-associated visceral adiposity, hyperinsulinemia, hyperglycemia, insulin-like growth factor (IGF-I) pathway as well as estrogen signaling and inflammation. Several of these factors are also involved in carcinogenesis and cancer progression. A better understanding of the link between metabolic syndrome and cancer may provide new insight about oncogenesis. Moreover, prevention of metabolic syndrome - related alterations may be an important aspect in the management of cancer patients during simultaneous palliative care

Hyperglycemia Promotes K-Ras-Induced Lung Tumorigenesis through BASCs Amplification

<div><p>Oncogenic K-Ras represents the most common molecular change in human lung adenocarcinomas, the major histologic subtype of non–small cell lung cancer (NSCLC). The presence of K-Ras mutation is associated with a poor prognosis, but no effective treatment strategies are available for K-Ras -mutant NSCLC. Epidemiological studies report higher lung cancer mortality rates in patients with type 2 diabetes. Here, we use a mouse model of K-Ras-mediated lung cancer on a background of chronic hyperglycemia to determine whether elevated circulating glycemic levels could influence oncogenic K-Ras-mediated tumor development. Inducible oncogenic K-Ras mouse model was treated with subtoxic doses of streptozotocin (STZ) to induce chronic hyperglycemia. We observed increased tumor mass and higher grade of malignancy in STZ treated diabetic mice analyzed at 4, 12 and 24 weeks, suggesting that oncogenic K-Ras increased lung tumorigenesis in hyperglycemic condition. This promoting effect is achieved by expansion of tumor-initiating lung bronchio-alveolar stem cells (BASCs) in bronchio-alveolar duct junction, indicating a role of hyperglycemia in the activity of K-Ras-transformed putative lung stem cells. Notably, after oncogene K-Ras activation, BASCs show upregulation of the glucose transporter (Glut1/Slc2a1), considered as an important player of the active control of tumor cell metabolism by oncogenic K-Ras. Our novel findings suggest that anti-hyperglycemic drugs, such as metformin, may act as therapeutic agent to restrict lung neoplasia promotion and progression.</p></div

HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma

BACKGROUND:Hypoxia and the subsequent activation of hypoxia-inducible factor-2α (HIF2α) contribute to the progression of a variety of cancers. However, their role in the generation of renal cell carcinoma-derived stem cells has not been fully addressed. METHODS:A sphere formation assay, cell proliferation, RT-PCR, western blot, FACS, immunohistochemistry and tumour xenograft were used to study the role of HIF2α. RESULTS:Propagation of four renal cell carcinoma (RCC) cell lines (Caki-1, Caki-2, 786-O, 769-P) in anchorage-independent floating spheres led to the expansion of cells bearing the CXCR4 (CD184) surface marker. Inhibition of the CXCR4 pathway reduced sphere expansion. The enhanced self-renewal activity of the CXCR4-positive spheres was preceded by the upregulation of HIF2α. Knockdown of HIF2α abrogated CXCR4 expression and sphere formation. Finally, RCC-derived spheres showed an undifferentiated phenotype in vivo and formed subcutaneous tumours that highly expressed HIF2α and CXCR4. Inhibition of HIF2α abolished tumour growth in animal models. CONCLUSIONS:These results suggest that the generation of RCC-derived CSCs involves the activation of HIF2α and may provide a foundation for the development of new strategies to prevent the induction of CSCs in RCC

HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma

BACKGROUND: Hypoxia and the subsequent activation of hypoxia-inducible factor-2α (HIF2α) contribute to the progression of a variety of cancers. However, their role in the generation of renal cell carcinoma-derived stem cells has not been fully addressed. METHODS: A sphere formation assay, cell proliferation, RT–PCR, western blot, FACS, immunohistochemistry and tumour xenograft were used to study the role of HIF2α. RESULTS: Propagation of four renal cell carcinoma (RCC) cell lines (Caki-1, Caki-2, 786-O, 769-P) in anchorage-independent floating spheres led to the expansion of cells bearing the CXCR4 (CD184) surface marker. Inhibition of the CXCR4 pathway reduced sphere expansion. The enhanced self-renewal activity of the CXCR4-positive spheres was preceded by the upregulation of HIF2α. Knockdown of HIF2α abrogated CXCR4 expression and sphere formation. Finally, RCC-derived spheres showed an undifferentiated phenotype in vivo and formed subcutaneous tumours that highly expressed HIF2α and CXCR4. Inhibition of HIF2α abolished tumour growth in animal models. CONCLUSIONS: These results suggest that the generation of RCC-derived CSCs involves the activation of HIF2α and may provide a foundation for the development of new strategies to prevent the induction of CSCs in RCC

Analysis of BASCs expansion.

<p><b>A.</b> Immunohistochemical analysis of CC10 and SP-C in terminal bronchioles of STZ-K-Ras^V12 (<b>i, ii</b>) and untreated-K-Ras^V12 (<b>iii, iv</b>) mice. Magnification 200×. Calibration bar: 50 µm. <b>B.</b> Bar graph indicates percentage of terminal bronchioles with 1 or more BASCs at early and late time (STZ-K-Ras^V12<i>vs</i> STZ-WT: *<i>p</i><0,01 by X² test).</p

Assessment of tumor development and progression of lung tumors in STZ-K-Ras^V12 mice compared to untreated-K-Ras^V12 ones.

<p><b>A.</b> Average number of tumors that developed per mouse in STZ-K-Ras^V12 (black bar) compared to untreated-K-Ras^V12 (white bar) mice. <b>B.</b> Average tumor size (mm²) in STZ-K-Ras^V12 (black bar) and in untreated-K-Ras^V12 mice (white bar). <b>C.</b> Expression of neoplastic tissue with the tumor burden index which considers average number of tumors per mice and average size. Data are presented as mean ± SEM, <i>*p</i><0.05 (Student's <i>t</i>-test).</p

Immunofluorescent staining of tissue sections to detect the Glut1 expression (red).

<p><b>A.</b> Terminal bronchioles of both STZ-K-Ras^V12 and untreated-K-Ras^V12 mice; <b>B.</b> Tumoral masses of STZ-K-Ras^V12 mice. Magnification 100×. Calibration bar: 100 µm.</p

Hibiscus Flower and Olive Leaf Extracts Activate Apoptosis in SH-SY5Y Cells

: Compounds of natural origin may constitute an interesting tool for the treatment of neuroblastoma, the most prevalent extracranial solid tumor in children. PRES is a commercially available food supplement, composed of a 13:2 (w/w) extracts mix of Olea europaea L. leaves (OE) and Hibiscus sabdariffa L. flowers (HS). Its potential towards neuroblastoma is still unexplored and was thus investigated in human neuroblastoma SH-SY5Y cells. PRES decreased the viability of cells in a concentration-dependent fashion (24 h IC50 247.2 ± 31.8 µg/mL). Cytotoxicity was accompanied by an increase in early and late apoptotic cells (AV-PI assay) and sub G0/G1 cells (cell cycle analysis), ROS formation, reduction in mitochondrial membrane potential, and caspases activities. The ROS scavenger N-acetyl-L-cysteine reverted the cytotoxic effects of PRES, suggesting a key role played by ROS in PRES-mediated SH-SY5Y cell death. Finally, the effects of OE and HS extracts were singularly tested and compared to those of the corresponding mixture. OE- or HS-mediated cytotoxicity was always significantly lower than that caused by PRES, suggesting a synergic effect. In conclusion, the present findings highlight the potential of PRES for the treatment of neuroblastoma and offers the basis for a further characterization of the mechanisms underlying its effects

Apoptotic-Induced Effects of Acacia Catechu Willd. Extract in Human Colon Cancer Cells

: The research for innovative treatments against colon adenocarcinomas is still a great challenge. Acacia catechu Willd. heartwood extract (AC) has health-promoting qualities, especially at the gastrointestinal level. This study characterized AC for its catechins content and investigated the apoptosis-enhancing effect in human colorectal adenocarcinoma HT-29 cells, along with its ability to spare healthy tissue. MTT assay was used to describe the time course, concentration dependence and reversibility of AC-mediated cytotoxicity. Cell cycle analysis and AV-PI and DAPI-staining were performed to evaluate apoptosis, together with ROS formation, mitochondrial membrane potential (MMP) changes and caspase activities. Rat ileum and colon rings were tested for their viability and functionality to explore AC effects on healthy tissue. Quantitative analysis highlighted that AC was rich in (±)-catechin (31.5 ± 0.82 mg/g) and (-)-epicatechin (12.5 ± 0.42 mg/g). AC irreversibly decreased cell viability in a concentration-dependent, but not time-dependent fashion. Cytotoxicity was accompanied by increases in apoptotic cells and ROS, a reduction in MMP and increases in caspase-9 and 3 activities. AC did not affect rat ileum and colon rings' viability and functionality, suggesting a safe profile toward healthy tissue. The present findings outline the potential of AC for colon cancer treatment