Cancer shows lowered pH, what does this indicate and why cancer cell prefer to do this? Is anything relevant or edge that it can get after making the acidic micro-environment?
Research Director, No Surrender Breast Cancer Foundation (NSBCF)
_____________________________________________________
I have done extensive research in this area of cancer metabolism so I will try to place the issue in a clinical context, and also add some highly intriguing and positive data from my own field of expertise, advanced breast cancer therapeutics; the discussion below represents a highly distilled summary of a recent internal review I conducted [pending publication]:
MICROENVIRONMENTAL ACIDOSIS
The phenomenon of microenvironmental acidosis, that is, acidification of the microenvironment, is known to facilitate tumor invasion through these three major mechanisms [1]:
(1) DESTRUCTION OF ADJACENT NORMAL CELL POPULATIONS
(2) ACID-INDUCED DEGRADATION OF THE EXTRACELLULAR MATRIX (ECM)
(3) ANGIOGENESIS PROMOTION
So we know that increased acid production from upregulation of glycolysis results in microenvironmental acidosis which facilitates invasion, and which happens because increased acid production leads to significant decreases in local extracellular pH, and prolonged exposure of normal cells to an acidic microenvironment results in either or both necrosis or apoptosis, through p53-dependent and caspase-3-dependent mechanisms [2,3], and there is evidence that diffusion of acid from the tumor into peritumoral normal tissue provides a specific mechanism promoting tumor invasion [4]. Thus, normal cells, by virtue of lacking a mechanism to adapt to extracellular acidosis (like p53 mutation) cannot survive under such conditions of microenvironmental acidosis, whereas tumor populations continue to proliferate.
HUMAN CLINICAL EVIDENCE
But more importantly, recent evidence from Matteo Bellone and colleagues [5] has shown that acidity per se represents a mechanism of immune escape, and that this mechanism of immune escape via the acidification of the tumor microenvironment can be overcome by drugs targeting pH-regulatory pathways, like PPIs (such as esomeprazole (Nexium) which was used in the study), which can increase the clinical potential of T cell-based cancer immunotherapy.
This is an exciting new area of therapeutic targeting: to target microenvironmental acidosis, which as shown above encourages tumor invasion and malignant transformation, by use of anti-secretory proton pump inhibitors (PPIs), in order to reduce or reverse acidification of the microenvironment and thus pro-tumorigenic and carcinogenic processes.
BREAKTHROUGH RESULTS IN METASTATIC DISEASE
And we now finally have human clinical data in confirmation of this approach: researchers at the Shanghai Cancer Center in China and at the National Institute of Health in Roma, Italy have presented results at the SABCS 2012 Conference of a randomized trial [6] investigating whether the efficacy of chemotherapy could be improved with the addition of high-dose proton pump inhibitor (PPI) therapy, in the form of esomeprazole (Nexium), in metastatic breast cancer patients. What they found was a significant improvement in profession-free survival (PFS) for the general population of metastatic breast cancer patients who were on PPI therapy compared to those who were not, and even more dramatically, in those metastatic breast cancer patients who had the most aggressive and prognostically unfavorable breast cancer subtype, namely triple negative breast cancer (TNBC), PFS was improved by almost three-fold over patients not on PPI therapy. These are breakthrough findings, and if further confirmed in Phase III trial results, represent both (1) a unique non-toxic intervention that can improved survival outcome in metastatic disease, and (2) significant confirmation of the cancer metabolism hypothesis, and in particular of the potential of microenvironmental acidosis to serve as a therapeutic target in advanced cancer, as per also several recent reviews [7,8]. [Note: I expect further confirmations to appear at the forthcoming SABCS 2013 Conference].
METHODOLOGY OF THIS REVIEW
A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) and SCIRUS databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using SCIRUS (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.
REFERENCES
1. Gatenby RA, Gillies RJ Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004; 4(11):891-9.
2. Park, H. J., Lyons, J. C., Ohtsubo, T. & Song, C. W. Acidic environment causes apoptosis by increasing caspase activity. Br. J. Cancer 1999; 80, 1892–1897.
3. Williams, A. C., Collard, T. J. & Paraskeva, C. An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis. Oncogene 1999; 18, 3199–3204.
4. Gatenby, R. A. & Gawlinski, E. T. A reaction-diffusion model of cancer invasion. Cancer Res. 1996; 56, 5745–5753.
5. Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. OncoImmunology 2012; 2:e22058.
6. Hu X, Wang B, Sun S, et al. Intermittent High Dose Proton Pump Inhibitor Improves Progression Free Survival as Compared to Standard Chemotherapy in the First Line Treatment of Patients with Metastatic Breast Cancer. Abstracts: Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symposium-- Dec 4-8, 2012; San Antonio, TX. Cancer Res December 15, 2012; 72(24 Supplement): P6-11-01.
7. De Milito A, Marino ML, Fais S. A rationale for the use of proton pump inhibitors as antineoplastic agents. Curr Pharm Des 2012; 18(10):1395-406.
8. Ivanov AA, Khuri FR, Fu H. Targeting protein-protein interactions as an anticancer strategy.
Trends Pharmacol Sci 2013; 34(7):393-400.
In my opinion the acidity is consequent to the Warburg effect predominant in cancer tissues
Low pH is an indication of carbonic acid and CO2 accumulation. Primary reason for that is incomplete oxidation due to high metabolic rate that is corroborated by insufficient blood circulation.
As Roberto pointed out with the Warburg effect, cancer cells which are often in low-oxygen environments (due initially to poor vacularization) do not complete glycolysis resulting in the accumulation of lactate/lactic acid.
It might be due to high ROS level they generate as a result of mitochondrial malfunctioning, high metabolic rate and hypoxia
Research Director, No Surrender Breast Cancer Foundation (NSBCF)
_____________________________________________________
I have done extensive research in this area of cancer metabolism so I will try to place the issue in a clinical context, and also add some highly intriguing and positive data from my own field of expertise, advanced breast cancer therapeutics; the discussion below represents a highly distilled summary of a recent internal review I conducted [pending publication]:
MICROENVIRONMENTAL ACIDOSIS
The phenomenon of microenvironmental acidosis, that is, acidification of the microenvironment, is known to facilitate tumor invasion through these three major mechanisms [1]:
(1) DESTRUCTION OF ADJACENT NORMAL CELL POPULATIONS
(2) ACID-INDUCED DEGRADATION OF THE EXTRACELLULAR MATRIX (ECM)
(3) ANGIOGENESIS PROMOTION
So we know that increased acid production from upregulation of glycolysis results in microenvironmental acidosis which facilitates invasion, and which happens because increased acid production leads to significant decreases in local extracellular pH, and prolonged exposure of normal cells to an acidic microenvironment results in either or both necrosis or apoptosis, through p53-dependent and caspase-3-dependent mechanisms [2,3], and there is evidence that diffusion of acid from the tumor into peritumoral normal tissue provides a specific mechanism promoting tumor invasion [4]. Thus, normal cells, by virtue of lacking a mechanism to adapt to extracellular acidosis (like p53 mutation) cannot survive under such conditions of microenvironmental acidosis, whereas tumor populations continue to proliferate.
HUMAN CLINICAL EVIDENCE
But more importantly, recent evidence from Matteo Bellone and colleagues [5] has shown that acidity per se represents a mechanism of immune escape, and that this mechanism of immune escape via the acidification of the tumor microenvironment can be overcome by drugs targeting pH-regulatory pathways, like PPIs (such as esomeprazole (Nexium) which was used in the study), which can increase the clinical potential of T cell-based cancer immunotherapy.
This is an exciting new area of therapeutic targeting: to target microenvironmental acidosis, which as shown above encourages tumor invasion and malignant transformation, by use of anti-secretory proton pump inhibitors (PPIs), in order to reduce or reverse acidification of the microenvironment and thus pro-tumorigenic and carcinogenic processes.
BREAKTHROUGH RESULTS IN METASTATIC DISEASE
And we now finally have human clinical data in confirmation of this approach: researchers at the Shanghai Cancer Center in China and at the National Institute of Health in Roma, Italy have presented results at the SABCS 2012 Conference of a randomized trial [6] investigating whether the efficacy of chemotherapy could be improved with the addition of high-dose proton pump inhibitor (PPI) therapy, in the form of esomeprazole (Nexium), in metastatic breast cancer patients. What they found was a significant improvement in profession-free survival (PFS) for the general population of metastatic breast cancer patients who were on PPI therapy compared to those who were not, and even more dramatically, in those metastatic breast cancer patients who had the most aggressive and prognostically unfavorable breast cancer subtype, namely triple negative breast cancer (TNBC), PFS was improved by almost three-fold over patients not on PPI therapy. These are breakthrough findings, and if further confirmed in Phase III trial results, represent both (1) a unique non-toxic intervention that can improved survival outcome in metastatic disease, and (2) significant confirmation of the cancer metabolism hypothesis, and in particular of the potential of microenvironmental acidosis to serve as a therapeutic target in advanced cancer, as per also several recent reviews [7,8]. [Note: I expect further confirmations to appear at the forthcoming SABCS 2013 Conference].
METHODOLOGY OF THIS REVIEW
A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) and SCIRUS databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using SCIRUS (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.
REFERENCES
1. Gatenby RA, Gillies RJ Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004; 4(11):891-9.
2. Park, H. J., Lyons, J. C., Ohtsubo, T. & Song, C. W. Acidic environment causes apoptosis by increasing caspase activity. Br. J. Cancer 1999; 80, 1892–1897.
3. Williams, A. C., Collard, T. J. & Paraskeva, C. An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis. Oncogene 1999; 18, 3199–3204.
4. Gatenby, R. A. & Gawlinski, E. T. A reaction-diffusion model of cancer invasion. Cancer Res. 1996; 56, 5745–5753.
5. Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. OncoImmunology 2012; 2:e22058.
6. Hu X, Wang B, Sun S, et al. Intermittent High Dose Proton Pump Inhibitor Improves Progression Free Survival as Compared to Standard Chemotherapy in the First Line Treatment of Patients with Metastatic Breast Cancer. Abstracts: Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer Symposium-- Dec 4-8, 2012; San Antonio, TX. Cancer Res December 15, 2012; 72(24 Supplement): P6-11-01.
7. De Milito A, Marino ML, Fais S. A rationale for the use of proton pump inhibitors as antineoplastic agents. Curr Pharm Des 2012; 18(10):1395-406.
8. Ivanov AA, Khuri FR, Fu H. Targeting protein-protein interactions as an anticancer strategy.
Trends Pharmacol Sci 2013; 34(7):393-400.
the strangeness Warburg effect is due to the fact that the cells carry out glycolysis (and consequent lactic fermentation and acidosis) even in the presence of large amounts of oxygen
I would also suspect it's due to accumulation of intracellular ROS in cancer cells, necessary for them to sustain the abnormally high metabolism rate. The anaerobic conditions of poorly vascularised tumour induce a metabolic switch from oxidative glucose metabolism to anaerobic glycolysis, i.e. the Warburg effect, therefore the ROS-resistance of cancer cells is higher than normal cells. To prevent development of toxic levels of ROS, cancer cells induce the antioxidant response element (ARE) and utilise extrinsic antioxidant species, making dietary antioxidants in fact anti-therapeutic (in advanced tumours). The commonly used cancer treatments, such as 5-fluorouracil (5-Fu) and oxaliplatin, are pro-oxidant and increase the concentration of intra-cellular ROS to toxic levels in tumour cells.
I recommend this review on the subject:
Sosa, V. et al. 2013 Oxidative stress and cancer: An overview. Ageing Research Reviews, 12(1), 376-390.
cancer cells thrive in an acidic environment. This is most likely due to the increased rate of metabolism within the cell. Most cells undergo cell death in acidic environments, but cancer cells able to subvert cell death by activation of genes necessary to exercise chronic autophagy.
Can it be possible because cancer cell follow anaerobic respiration which produce more lactic acid and ultimately leads to acidic micro-environment.
Some great comments, esp by Kaniklidis. My thoughts taken verbatim from a protocol I authored involving treating cancer patients with an agent that blocks the Warberg effect.
The metabolic profile of malignancy is one associated with various metabolic adaptations that preferentially utilize the pathways involved with glycolysis. This is termed the glycolytic phenotype (GP) of cancer.2-4 In this Darwinian adaptation, the cancer cell diminishes, as well as undermines, the metabolic pathways of glucose oxidation (GO) used by normal cells for energy production as well as tumor cell elimination.3
Thus, it appears that cancer is a microcosmic obsession with energy with dire consequences to the host in that the GP predominates and subjugates the oxygen utilizing processes of the TCA and affiliated processes. Additionally, as part of the tumor’s adaptation to survival, the GP induces mitochondrial dysfunction resulting in diminished pro-apoptotic ability, which leads to increased survival of the cancer cell population. The GP also creates an acidotic cellular milieu which favors tumor cell hypoxia, survival, metastasis and also resistance to conventional anti-cancer treatments.3-6
The metabolism of the cancer cell may simply be an expression of energy needs developing in response to a hypoxic environment.7 Glycolysis became a favored metabolic pathway for the cancer cell population to adapt to hypoxia, and because it returned the cell to a more primitive state avoiding mitochondrial-related apoptotic pathways. Moreover, the oxidative pathways generate reactive oxygen species (ROS) that are associated with free-radical damage to the cancer cell. Again, this survival mechanism involves an attempt to immortalize the cancer cell by preventing ROS induced damage as well as to down-regulate the process of apoptosis.
In summary, cancer is an adaptive mechanism providing for extended survival of the cancer cell and, at the same time, meeting its energy requirements.5 Furthermore, the acid environment associated with the GP enables the cancer cell to breakdown extra-cellular matrix and invade local tissues, and subsequently metastasize to distant sites.8 Acidosis also favors resistance to radiation therapy and to anthracycline chemotherapy with agents like Adriamycin & Mitoxantrone. This is cancer's approach to survival of the fittest.
References cited above
2. Bui T, Thompson CB: Cancer's sweet tooth. Cancer Cell 9:419-420, 2006.
3. Fang JS, Gillies RD, Gatenby RA: Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol 18:330-337, 2008.
4. Gatenby RA, Gawlinski ET: The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models. Cancer Res 63:3847-3854, 2003.
5. Gatenby RA, Gillies RJ: Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4:891-899, 2004.
6. Gatenby RA, Smallbone K, Maini PK, et al: Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer 97:646-653, 2007.
7. Smallbone K, Gatenby RA, Gillies RJ, et al: Metabolic changes during carcinogenesis: potential impact on invasiveness. J Theor Biol 244:703-713, 2007.
8. Gatenby RA, Gawlinski ET, Gmitro AF, et al: Acid-mediated tumor invasion: a multidisciplinary study. Cancer Res 66:5216-5223, 2006.
Cancerous cells are unable to generate their ATP through the aerobic glycolytic pathway, therefore they try to compensate for that through anaerobic facet. The product is lactic acid and the accumulation of this lactic acid leads to a low pH. What gives the microenvironment of cancerous cells their acidity is Lactic acid.
I am sorry to disagree with Dr Temitope Adelusi. Cancer cells retain the possibility of OX-PHOS. As a matter of fact Warburg found that almost 50% of energy in cancer cells came from oxydative phosphorylation. The other 50% came from aerobic glycolysis.
Aerobic glycolysis is not the consequence of COMPENSATION DUE TO ENERGY SHORTAGE, but it is the direct result of oncogenic mutations and oncogenic pathways that enhance the expression of glycolyic enzymes. Increased expression of HIF 1 is an important responsible of the whole process of aerobic glycolisis and represents a consequence of oncogenic mutations.
Increased extracellular acidity with normal or slightly alkaline intracellular pH is a consequence of increased intracellular acid production (through hydrolisis of ATP) that is quickly exported to the extracelluar media thanks to incresed expression and increased activity of ion transporters like NHE-1 and VGSCs and proton pumps. All these transporters are highly expressed on the invadopodia complex.
The 'why/how' conundrum to cancer's pH hallmark starts making a lot more sense when we look at acid base from the perspective of the Stewart Kellum model. You should be able to source the 2nd edition of the Stewart Kellum book in your medical school/university library. There are a number of Stewart papers too on CO2/SIG/TotWeak Acid ...and here is a website http://www.acidbase.org
Peritumoral acidity is immunosuppressive and helps tumors to evade immune responses.
To serve tumor fitness.
Tumor acidity blunts immune system, mediates cancer chemotherapy resistance and develops metastasis.
Khalid
http://www.ncbi.nlm.nih.gov/pubmed/24310355/
So mutations are responsible of the activation of pathways able to enhance glycolytic enzymes leading to the glycolitic phenotype (metabolic reprogramming) of cancer cells. Cancer cells will produce energy mainly by glycolysis and lactate production rather than glycolysis followed by oxidation of piruvate in mitochondria (Warburg Effect), even if oxygen levels are normal. Lactate and protons begin to accumulate leading to acidosis.
It is known that hypoxia is able to induce the expression of HIF (Hipoxia Inducible Factor) that controls the expression of certain genes including several glycolytic enzymes and glucose transporters that will contribute to the Warburg Effect
But is hypoxia a consequence of the insufficient supply of oxygen due to rapidly proliferating tumor cells or are there other reasons?
Lactate exportation from cancer cells is the responsible for the acidic microenvironment of cancer cells. Lactate is the obligatory by-product of glycolysis and the Warburg effect increases glycolysis and therefore lactate production. Lactate is further exported from cancer cells by MCT-1 and MCT-4 transporters. This acidic environment inhibits immune response and also regulates exosomes production, therefore highly involved in the regulation of metastasis.
My understanding is that the acidic microenvironment of cancer cells is a consequence of their metabolic state. Cancer cells are predominantly glycolytic, leading to the production of lactic acid. Although glycolysis is less efficient at generating ATP when compared to mitochondrial OXPHOS, proliferative cells prefer glycolysis because in addition to ATP it also provides most of the building blocks required for cell proliferation.
Here is a paper showing that when glucose is no longer available cells switch from glycolysis to OXPHOS, resulting in the cessation of cell proliferation.
Article Circumventing the Crabtree Effect: A method to induce lactat...
Alexandra I Mot : I think you're talking about the oxidative phenotype. I'd suggest :
http://www.mdpi.com/2072-6694/3/3/3002/htm
In actively proliferating tumors, cells distant from blood vessels become hypoxic because of insufficient oxygen supply. As anaerobic glycolysis is the major source of energy in these hypoxic cells, the accumulation of lactate, a final metabolite of glycolysis, makes these cells acidic. These hypoxic and acidic cells are resistant to radiotherapy, and these tumors can recur when the tumor cells become reoxygenated after the tumor volume is reduced.
If such hypoxic and acidic cells could be radiosensitized, recurrence might be reduced and the effects of radiotherapy be improved. We previously showed that a low pH culture condition enhances the radiosensitizing effect of wortmannin (PI-3K inhibitor).
Article A low-pH culture condition enhances the radiosensitizing eff...
- Badges
- Science topic