Cholesterol esters as growth regulators of lymphocytic leukaemia cells.

OBJECTIVE: Alterations in plasma lipid profile and in intracellular cholesterol homoeostasis have been described in various malignancies; however, significance of these alterations, if any, in cancer biology is not clear. The aim of the present study was to investigate a possible correlation between alterations in cholesterol metabolism and expansion of leukaemia cell numbers. MATERIALS AND METHODS: Lipid profiles in plasma and in primary leukaemia cells isolated from patients with acute or chronic lymphocytic leukaemia (ALL and CLL) were studied. RESULTS AND CONCLUSIONS: Decreased levels of HDL-C were observed in plasma of leukaemic patients, levels of total cholesterol, LDL-C, triglycerides and phospholipids were unchanged or only slightly increased. As compared to normal lymphocytes, freshly isolated leukaemic cells showed increased levels of cholesterol esters and reduction in free cholesterol. Growth stimulation of ALL and CLL cells with phytohemagglutinin led to further increase in levels of cholesterol esters. Conversely, treatment with an inhibitor of cell proliferation such as the mTOR inhibitor, RAD, caused decline in population growth rate of leukaemia cells, which was preceded by sharp reduction in rate of cholesterol esterification. On the other hand, exposure of leukaemic cells to two inhibitors of cholesterol esterification, progesterone and SaH 58-035, caused 60% reduction in their proliferation rate. In addition to demonstrating tight correlation between cell number expansion and cholesterol esterification in leukaemic cells, these results suggest that pathways that control cholesterol esterification might represent a promising targets for novel anticancer strategies.

G6PD activity and gene expression in leukemic cells from G6PD-deficient subjects.

In the present study we examined gene expression and glucose-6-phosphate dehydrogenase (G6PD) activity in leukemic cells isolated from G6PD normal and deficient subjects. The results have shown that G6PD activity strongly increases in G6PD normal leukemic cells as well as in G6PD deficient leukemic cells when compared to peripheral blood mononuclear cells (PBMC). Higher levels of G6PD gene expression were observed in leukemic cells from G6PD deficient patients compared to G6PD normal. A similar pattern of gene expression was also observed for 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase. These results support the hypothesis that G6PD deficient cell, in order to sustain their growth, must respond to the low activity of their mutant enzyme with an increase in quantity through an induction of gene expression.

Cholesterol content in tumor tissues is inversely associated with high-density lipoprotein cholesterol in serum in patients with gastrointestinal cancer.

BACKGROUND: The authors have previously demonstrated in different experimental models that sustained processes of cellular growth are characterized by alterations of cholesterol metabolism not only in the proliferating tissues but also in the plasma compartment. METHODS: To evaluate whether alterations of cholesterol metabolism similar to those observed in experimental models are also associated with human cancer, in the present study cholesterol distribution in tumor tissues and lipid composition in the plasma compartment were determined in patients with different types of gastrointestinal cancer. RESULTS: The results showed that tumor tissues contain increased amounts of cholesterol when compared with the corresponding normal tissues. Intracellular alterations of cholesterol were accompanied by specific changes of cholesterol in the plasma compartment: high-density lipoprotein (HDL) cholesterol was markedly reduced in the serum of patients with gastrointestinal cancer and the lipoprotein profiles showed a decrease in HDL3 fraction, the main HDL subfraction in human serum. The decrease of HDL cholesterol was negatively associated with the clinical stage of the disease. No changes in either total or low-density lipoprotein cholesterol levels were observed. CONCLUSIONS: A major function attributed to HDL is to maintain normal cell cholesterol homeostasis by removing excess of cholesterol from intracellular pools. Because the use and storage of cholesterol are increased within the tumor tissues during growth, it is possible to hypothesize that low HDL levels observed in patients with gastrointestinal cancer are associated with the increased cholesterol metabolism in proliferating tissues.

Serum lipoprotein pattern as modified in G6PD-deficient children during haemolytic anaemia induced by fava bean ingestion.

In the present study, plasma lipid concentrations were determined at different times after admission in sera from G6PD-deficient children during haemolytic crisis induced by fava bean ingestion. Reductions in total, LDL and HDL cholesterol were found in association with the maximum of bone marrow hyperplasia. A return towards normal values occurred with regression of the disease. No changes in other lipid parameters were observed. These data suggest that alterations of lipoprotein pattern, other than in experimental animals, are also present in humans with non-malignant proliferative processes. These changes appear to be a consequence of the disease, probably due to an increased utilization of cholesterol by proliferating cells.

Altered pattern of lipid metabolism in patients with lung cancer.

Cholesterol distribution in tumoral tissues and lipid composition in the plasma compartment were determined in patients affected by different histologic types of lung cancer. The results showed that tumoral lung tissues contained 2-fold more total cholesterol and 3.5-fold more esterified cholesterol than normal lung tissues. In the patients the alterations in intracellular cholesterol were also associated with peculiar changes in cholesterol distribution in the plasma compartment. Serum high-density lipoprotein (HDL) cholesterol levels were markedly lower in than in controls. No significant changes in other lipid parameters were observed in these patients. We suggest that the reduced levels of serum HDL cholesterol observed in patients with lung tumors may be a consequence of the disease, probably mediated by the greater utilization of cholesterol for new membrane biogenesis and by the accumulation of esterified cholesterol in tumoral tissues.

Total and HDL cholesterol in human hematologic neoplasms.

In this study serum cholesterol was measured in different types of human hematologic malignancies characterized by a wide range of cell proliferation. In all tumoral types a significant decrease of HDL cholesterol was observed, whereas total serum cholesterol generally remained unchanged. Another interesting observation of our study was the apparent inverse correlation between the extent of cell proliferation in these neoplastic disorders and the level of HDL cholesterol. Since a decrease of HDL cholesterol was previously observed, in our laboratory, in different experimental models of normal and neoplastic cell proliferation, we suggest that the decrease of HDL cholesterol may be a generalized phenomenon related to massive cellular growth in normal and malignant processes.

Serum lipoproteins during bone marrow hyperplasia after phenylhydrazine administration in rats.

In the present study, lipoprotein metabolism was investigated during compensatory hyperplasia of bone marrow after haemolysis induced by phenylhydrazine (20 mg/kg b.w.) administration in rats. The rats were sacrificed at different time intervals (0, 1, 2 and 5 days) after phenylhydrazine treatment. Analysis of the different fractions of lipoproteins has shown that during bone marrow hyperplasia there is an alteration of lipoprotein profiles, mainly due to a decrease of HDL2 and HDL3 subfractions.

Modifying influence of fasting on liver hyperplasia induced by lead nitrate.

Previous studies by our laboratory have shown that lead nitrate when injected intravenously as a single dose to rats, induces a hyperplastic response in the liver. Liver hyperplasia was accompanied by an increase in cholesterol synthesis, an accumulation of cholesterol esters and by a stimulation of hexose-monophosphate (HMP) shunt enzyme activities. In the present report, hepatic DNA, mitotic index, cholesterol metabolism, as well as glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) activities, were investigated during liver hyperplasia induced by lead in fasted rats. Fasting was chosen as an experimental model characterized by a very strong depression of those metabolic pathways (cholesterol synthesis and HMP shunt) that we have found related to liver hyperplasia. The mitogenic response, even if at minor extent, also occurs in liver of fasted rats. A stimulation of cholesterol synthesis and HMP shunt enzyme activities, was also observed in lead-treated fasted rats, adding further support to the fact that an endogenous source of newly synthesized cholesterol together with a suitable increase of HMP shunt enzyme activities is needed during hepatic cell proliferation.

Multiple molecular forms of rat liver glucose-6-phosphate dehydrogenase during liver hyperplasia induced by lead nitrate.

In the present study the three dimeric molecular forms of rat liver glucose-6-phosphate dehydrogenase were investigated during liver hyperplasia induced by lead nitrate. An increase of band 3 and a concomitant decrease of band 1 was found, indicating that this proliferating process is characterized by a peculiar pattern in the distribution of liver G6PD activity. Since the same pattern was observed also in liver hyperplasia induced in fasted animals, a condition otherwise characterized by a shift towards band 1, we suggest that during proliferating processes the metabolic control normally exerted by fasting on the enzymatic activity is overcome.

Variations of serum lipoproteins during cell proliferation induced by lead nitrate.

In the present study serum lipoproteins were investigated during cell proliferation induced by a potent mitogen, lead nitrate. A strong decrease in HDL2 and a concomitant increase in HDL3 were observed in lead-treated rats. The recovery of normal lipoprotein pattern took place together with the regression of hyperplastic process. Since a decrease in HDL also occurs under other conditions of cell growth, we hypothesize that a decrease in HDL, mainly in HDL2 subfraction, may represent a generalized phenomenon related to massive cell proliferation.

Relationship between DNA and cholesterol synthesis in kidney after refeeding.

DNA and cholesterol synthesis were investigated in the kidneys of fasted-refed rats. Refeeding resulted in an increase in kidney DNA synthesis, as measured by 3H-thymidine incorporation, starting at 72 h. The increase in DNA synthesis was accompanied by a stimulation of cholesterol synthesis, as measured by 14C-acetate incorporation into cholesterol.