Abstract
Acidic extracellular pH (pHe) is an important microenvironment for cancer cells. This study assessed whether adaptation to acidic pHe enhances the metastatic phenotype of tumor cells. The low metastatic variant of Lewis lung carcinoma (LLCm1) cells were subjected to stepwise acidification, establishing acidic pHe-adapted (LLCm1A) cells growing exponentially at pH 6.2. These LLCm1A cells showed increased production of matrix metalloproteinases (MMPs), including MMP-2, -3, -9, and -13, and pulmonary metastasis following injection into mouse tail veins. Although LLCm1A cells exhibited a fibroblastic shape, keratin-5 expression was increased and α-smooth muscle actin expression was reduced. Despite serial passage of these cells at pH 7.4, high invasive activity through Matrigel® was sustained for at least 28 generations. Thus, adaptation to acidic pHe resulted in a more invasive phenotype, which was sustained during passage at pH 7.4, suggesting that an acidic microenvironment at the primary tumor site is important in the acquisition of a metastatic phenotype.
Highlights
IntroductionIn the presence of oxygen, lactic acid is the main cause of extracellular acidification, a process called the “Warburg effect” or “aerobic glycolysis” [1]
Extracellular pH (pHe) becomes acidic due to excess cellular glycolysis
Metastatic activity has been associated with the tumor microenvironment, which consists of growth factors, the extracellular matrix, hypoxia, and acidic p He
Summary
In the presence of oxygen, lactic acid is the main cause of extracellular acidification, a process called the “Warburg effect” or “aerobic glycolysis” [1]. Among lactate anion/ H+ symporters, known as monocarboxylate transporters (MCTs), the hypoxia-inducible subtype MCT4 is primarily responsible for the secretion of lactic acid. HIF-1 activation in tumors up-regulates angiogenesis and/or lymphangiogenesis. These newly formed vessels provide primary tumor cells the opportunity to disseminate through the circulation [5]. Acidic p He induces the production of vascular endothelial cell growth factor (VEGF)-A [6], interleukin-8 (IL-8) [7], and VEGF-C [8] through an HIF-1 independent pathway. An acidic pHe microenvironment, whether independent of, in addition to, or synergistically with hypoxia, may support the malignant phenotype of cancer cells and play a role in metastasis
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