The mechanisms by which polyamines accelerate tumor spread

Abstract

Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions.

Figure 1

Polyamine biosynthesis, degradation, and transmembrane transport. The polyamines spermine and spermidine are synthesized from arginine. Arginase converts arginine to ornithine, and ornithine decarboxylase (ODC) catalyzes decarboxylation of ornithine to form putrescine, a polyamine precursor containing two amine groups. ODC, a rate-limiting enzyme with a short half-life, is inhibited by antizyme, and antizyme is inhibited by an antizyme inhibitor. S-adenosylmethionine decarboxylase (AdoMetDC) is the second rate-limiting enzyme in polyamine synthesis and is involved in the decarboxylation of S-adenosylmethionine. Spermidine synthetase and spermine synthase are constitutively expressed aminopropyltransferases that catalyze the transfer of the aminopropyl group from decarboxylated S-adenosylmethionine to putrescine and spermidine to form spermidine and spermine, respectively. Polyamine degradation is achieved by spermine/spermidine N¹-acetyltransferase (SSAT) and N¹-acetylpolyamine oxidase (APAO). In addition, spermine oxidase (SMO) specifically oxidizes spermine. Polyamines are transported across the membrane transmembrane by the polyamine transporter.

Figure 2

Mechanism of cancer metastasis. A. Cancer cells produce proteases to destroy the surrounding matrix, and produce proteins to create new vessels. In cancer tissues, there are areas where the oxygen supply is poor, which induces hypoxia. Hypoxic cancer cells lose their adhesion characteristics and have enhanced capacity for migration. B. (1) Polyamines synthesized by cancer cells are transferred to cancer cells under hypoxic conditions that have increased capacity for polyamine uptake and decreased intracellular polyamine synthesis. The increase in polyamine concentration due to increased polyamine uptake decreases adhesion of cancer cells by decreasing adhesion molecule expression. (2) Polyamines are transferred to the blood cells. Increased polyamine uptake by immune cells results in decreased production of tumoricidal cytokines and the amount of adhesion molecules, and these eventually attenuate the cytotoxic activities of immune cells.