Acidity Generated by the Tumor Microenvironment Drives Local Invasion

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Estrella V, Chen T, Lloyd M, et al. Cancer Res March 1, 2013 73; 1524. doi: 10.1158/0008-5472.CAN-12-2796

The propensity of cancers to invade adjacent normal tissues contributes significantly to local tumor growth and formation of metastases, which are largely responsible for tumor-associated morbidity and mortality (1). The mechanisms by which tumor cells invade are complex and can be modified in response to environmental conditions (2). Because of increased glucose metabolism, H+ production and excretion are generally increased in cancers (3). This, combined with poor perfusion, results in an acidic extracellular pH (pHe) in malignant tumors (pH 6.5–6.9) compared with normal tissue under physiologic conditions (pHe 7.2–7.4; refs. 4–6). Acidic pHe can induce release of (cysteine or aspartyl) cathepsin proteinase activity in vitro (7–9), which is generally believed to be involved in local invasion and tissue remodeling (10–12). Furthermore, cells exposed to in vitro low pH show increased invasion both in vitro and in vivo (9, 13, 14). These observations are synthesized in the acid-mediated invasion hypothesis, wherein H+ ions flow along concentration gradients from tumor into adjacent normal tissue, promoting tissue remodeling at the tumor–stroma interface (15). The resulting acidic environment is toxic to normal cells, promotes a degradation of the extracellular matrix by proteinases (16), increases angiogenesis through the release of VEGF, and inhibits the immune response to tumor antigens (17–19). Cancer cells, because of their enhanced evolutionary capacity, develop adaptive mechanisms that allow them to survive and even proliferate in acidic environments (20). These adaptations can involve, inter alia, upregulation of the sodium-hydrogen exchanger-1 (NHE-1) or carbonic anhydrase (CA-IX; refs. 21–23). As normal cells die and the extracellular matrix is degraded, cancer cells continue to proliferate and invade this open space. Thus, we propose that the acidic pH of the tumor microenvironment represents a niche engineering strategy that promotes local invasion and subsequent in vivo growth of malignant tumors. Support for this model has come from recent observations that neutralization of the tumor-derived acid with systemic buffers (e.g., bicarbonate, imidazole, lysine, etc.), can inhibit spontaneous and experimental metastases (8, 24, 25). Here, we explicitly examine the acid-mediated invasion model by correlating regional variations in peritumoral acidity with subsequent patterns of tumor invasion.

An important tool to investigate acid-mediated invasion is the dorsal window chamber, first developed in 1987 (26). We have previously used this system to test aspects of the acid mediated invasion hypothesis and have quantitatively measured the export of tumor-derived acid into surrounding stroma (16). In addition, dorsal window chambers were used to observe a measureable decrease in tumor–stroma pH gradient following oral NaHCO3 treatment, which has been shown to reduce formation of spontaneous or experimental metastases (8). In the current work, we observed that the acidic pHe of peritumoral tissues was coincident with the location of subsequent tumor invasion, which is a specific prediction of the acid-mediated invasion hypothesis. Furthermore, bicarbonate treatment reduced the pH gradient and prevented invasion completely. Thus, the current findings are directly supportive of the acid-mediated invasion hypothesis.

The pH of solid tumors is acidic due to increased fermentative metabolism and poor perfusion. It has been hypothesized that acid pH promotes local invasive growth and metastasis. The hypothesis that acid mediates invasion proposes that H+ diffuses from the proximal tumor microenvironment into adjacent normal tissues where it causes tissue remodeling that permits local invasion. In the current work, tumor invasion and peritumoral pH were monitored over time using intravital microscopy. In every case, the peritumoral pH was acidic and heterogeneous and the regions of highest tumor invasion corresponded to areas of lowest pH. Tumor invasion did not occur into regions with normal or near-normal extracellular pH. Immunohistochemical analyses revealed that cells in the invasive edges expressed the glucose transporter-1 and the sodium–hydrogen exchanger-1, both of which were associated with peritumoral acidosis. In support of the functional importance of our findings, oral administration of sodium bicarbonate was sufficient to increase peritumoral pH and inhibit tumor growth and local invasion in a preclinical model, supporting the acid-mediated invasion hypothesis.

The morbidity and mortality associated with cancer is largely related to tumor invasion and formation of metastases. Extensive application of 2[18F]fluoro-2-deoxy-d-glucose–positron emission tomography (FDG-PET) imaging to clinical cancers has clearly shown the vast majority of malignant tumors metabolize glucose at high rates. (26,27). We propose there is a direct, causative link between increased glucose metabolism and the ability of cancer cells to invade and metastasize.Elevated glucose metabolism is the proximate cause of increased acidity in the tumor microenvironment. Furthermore, most tumors develop an aberrant vasculature network that tends to be poorly organized and leaky, disrupting blood flow, and hampering the delivery of oxygen (28). This has a 2-fold effect on tumor acidity. First, it subjects tumor regions to poor perfusion, and hence poor oxygenation (37). Low oxygenation increases glycolytic flux via the Pasteur effect. Notably, even in tumor regions with adequate oxygen supply, glycolysis and acid production are upregulated via the Warburg effect. Second, poor perfusion hampers the ability of the microenvironment to remove tumor derived acid through diffusion. Consequently, the pHe of tumors is typically highly acidic, and this will inevitably result in acid diffusion into the surrounding stroma.
We have previously proposed that the invasive phenotype and increased glucose metabolism are, in fact, closely linked (23). Much of this work stems from viewing cancer biology as an ecologic and evolutionary process. Within this context, all commonly observed phenotypes in cancers must be conferring an evolutionary advantage. In this case, we ask “how does increased glucose metabolism and consequent interstitial acidosis confer an evolutionary advantage that promotes tumor cell proliferation?” This has led to the proposal that regional acidosis represents a strategy commonly observed in nature as niche engineering in which plants and animal alter their environment in ways that promote their own growth and survival and/or diminishes that of their competitors. The conceptual model that tumors use increased glucose metabolism, even in the presence of adequate oxygen, as a form of niche engineering is the basis of the acid-mediated invasion hypothesis (15, 16). The model assumes that through evolutionary events during carcinogenesis, as cancer cells proliferate on epithelial surfaces , they must adapt to increased acid production by expression of proton export systems, such as NHE-1 or CA-IX, which transport H+ from intra- to extracellular space, resulting in extracellular acidification. However, normal mammalian tissue, lacking the evolutionary capacity of cancer cells, typically remains intolerant of prolonged exposure to acidic pH. This model posits H+ flows along concentration gradients, from the tumor into the peritumoral normal tissue, causing disruption that favors subsequent tumor growth. A variety of studies have shown that an acidic peritumoral pH is associated with a degradation of the extracellular matrix, possibly through the release and activation of proteolytic enzymes (7, 16). The low pH also leads normal cells to undergo apoptosis and necrosis, whereas cancer cells survive due to acquired resistance mechanisms (31, 32). In summary, regional acidosis causes substantial niche engineering through normal cell death, breakdown of extracellular matrix, promotion of new vessel formation, and suppression of the immune response (10, 17, 18).

The results of this study suggest that tumor cells do, indeed, perform niche engineering by creating an acidic environment that is nontoxic to the malignant cells, but through its negative effects on normal cells and tissue, promotes local invasion. Targeting this evolutionary strategy through systemic buffers and other mechanisms to reduce peritumoral pH will likely provide a valuable adjunct or alternative to traditional therapies focused entirely on killing the tumor cells.

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Effect of methanol extracts of Cnidium officinale Makino and Capsella bursa-pastoris on the apoptosis of HSC-2 human oral cancer cells.

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Cnidium Officinale

Lee KE, Shin JA, Hong IS, Cho NP, Cho SD. Exp Ther Med. 2013 Mar;5(3):789-792. Epub 2012 Dec 21.
Cnidium officinale Makino and Capsella bursa-pastoris are used as traditional herbs with diverse medicinal effects, including the inhibition of inflammation, reduction of blood pressure and as diuretics, however, the anti-cancer effects of C. officinale Makino and C. bursa-pastoris are poorly defined. The aims of this study were to evaluate the effects of methanol extracts of C. officinale Makino (MECO) and methanol extracts of C. bursa-pastoris (MECB) on the cell growth and apoptosis of HSC-2 human oral cancer cells. MECO and MECB caused growth inhibition and the induction of apoptosis in a concentration-dependent manner in HSC-2 cells.
A marked reduction in specificity protein 1 (Sp1) expression following treatment with MECO or MECB was also observed. The downregulation of Sp1 by siRNA resulted in growth inhibition and a reduction of total poly (ADP-ribose) polymerase (PARP) expression. In addition, MECO significantly increased Bax expression levels and MECB increased Bak expression levels and decreased Mcl-1 expression levels. These results suggest that MECO and MECB inhibit cell growth and induce apoptosis via the Sp1 protein, indicating that MECO and MECB are useful bioactive materials and attractive drug candidates for oral cancer.

Their musical renditions of today hits cover songs from

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Subamolide A Induces Mitotic Catastrophe Accompanied by Apoptosis in Human Lung Cancer Cells

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Hung J-Y, Wen C-W, Hsu Y-L, et al. Evidence-Based Complementary and Alternative Medicine. Volume 2013 (2013),


This study investigated the anticancer effects of subamolide A (Sub-A), isolated from Cinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS) production and decreased glutathione level.

The elevated ROS triggered the activation of ataxia-telangiectasia mutation (ATM), which further enhanced the ATF3 upregulation and subsequently enhanced p53 function by phosphorylation at Serine 15 and Serine 392. The antioxidant, EUK8, significantly decreased mitotic catastrophe by inhibiting ATM activation, ATF3 expression, and p53 phosphorylation.

The reduction of ATM and ATF3 expression by shRNA decreased Sub-A-mediated p53 phosphorylation and mitotic catastrophe. Sub-A also caused a dramatic 70% reduction in tumor size in an animal model. Taken together, cell death of lung cancer cells in response to Sub-A is dependent on ROS generation, which triggers mitotic catastrophe followed by apoptosis. Therefore, Sub-A may be a novel anticancer agent for the treatment of nonsmall cell lung cancer.

Human lung cancer cells A549 and NCI-H460 are highly sensitive to Sub-A-induced mitotic catastrophe and apoptosis, mainly via ROS elevation that induces ATM and ATF3 activation, subsequently leading to p53-mediated cell death. Sub-A also causes cell growth inhibition in an in vivo xenograft model. The elucidated molecular bases and processes may provide a new strategy for developing more effective chemotherapeutic regimens for lung cancer treatment.