Abstract
While cancer is commonly described as “a disease of the genes,” it is also associated with massive metabolic reprogramming that is now accepted as a disease “Hallmark.” This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer’s metabolic program can improve patients’ outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as “aerobic glycolysis” or the “Warburg Effect.” Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place.
| Original language | English |
|---|---|
| Pages (from-to) | 205-222 |
| Number of pages | 18 |
| Journal | Cancer and Metastasis Reviews |
| Volume | 38 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - Jun 15 2019 |
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Keywords
- Anti-acidic therapy
- Cancer
- Exosomes
- Microenvironment acidity
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Causes, consequences, and therapy of tumors acidosis. / Pillai, Smitha R.; Damaghi, Mehdi; Marunaka, Yoshinori; Spugnini, Enrico Pierluigi; Fais, Stefano; Gillies, Robert J.
In: Cancer and Metastasis Reviews, Vol. 38, No. 1-2, 15.06.2019, p. 205-222.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Causes, consequences, and therapy of tumors acidosis
AU - Pillai, Smitha R.
AU - Damaghi, Mehdi
AU - Marunaka, Yoshinori
AU - Spugnini, Enrico Pierluigi
AU - Fais, Stefano
AU - Gillies, Robert J.
PY - 2019/6/15
Y1 - 2019/6/15
N2 - While cancer is commonly described as “a disease of the genes,” it is also associated with massive metabolic reprogramming that is now accepted as a disease “Hallmark.” This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer’s metabolic program can improve patients’ outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as “aerobic glycolysis” or the “Warburg Effect.” Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place.
AB - While cancer is commonly described as “a disease of the genes,” it is also associated with massive metabolic reprogramming that is now accepted as a disease “Hallmark.” This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer’s metabolic program can improve patients’ outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as “aerobic glycolysis” or the “Warburg Effect.” Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place.
KW - Anti-acidic therapy
KW - Cancer
KW - Exosomes
KW - Microenvironment acidity
UR - http://www.scopus.com/inward/record.url?scp=85064176240&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064176240&partnerID=8YFLogxK
U2 - 10.1007/s10555-019-09792-7
DO - 10.1007/s10555-019-09792-7
M3 - Review article
C2 - 30911978
AN - SCOPUS:85064176240
VL - 38
SP - 205
EP - 222
JO - Cancer and Metastasis Reviews
JF - Cancer and Metastasis Reviews
SN - 0167-7659
IS - 1-2
ER -