为什么癌症有酸性的微环境?

Why does cancer have an acidic microenvironment?

 

 

 

 

肿瘤组织呈酸性,这说明了什么?为什么癌细胞更喜欢这样做? 在制造出酸性微环境后,它能得到什么相关的或有利于生存的东西吗?

 

 

 

我在癌症代谢这一领域做了广泛的研究,所以我将尝试把这个问题放在临床背景下,并加入一些非常有趣和积极的数据,来自我自己的专业领域,晚期的乳腺癌治疗;下面的讨论是我最近进行的(待发表的)一次内部审查的高度总结:

微环境酸中毒

微环境酸中毒现象,即微环境酸化,通过这三种主要机制促进肿瘤侵袭:

(1)相邻正常细胞群的破坏

(2)酸诱导细胞外基质降解(ECM)

(3)促进血管生成

 

所以我们知道增加糖酵解的上调,产酸的增加导致微环境酸中毒促进肿瘤侵袭。因为酸产量的增加会导致局部细胞外液的pH值的显著降低, 正常细胞长时间接触酸性微环境,通过依赖于p53 caspase 3机制导致坏死或凋亡。有证据表明,酸从肿瘤向肿瘤周正常组织的扩散提供了促进肿瘤侵袭的特定机制。因此,正常细胞由于缺乏适应细胞外酸中毒(p53突变)的机制,无法在微环境酸中毒的条件下存活,而肿瘤群体继续增殖。

 

 

 

人类的临床证据

但更重要的是,最近从Matteo Bellone和同事的证据表明, 酸性本身代表一个免疫逃避机制,这种机制的免疫逃避通过肿瘤微环境的酸化可以针对pH-调控途径的药物,如质子泵抑制剂(如唑(埃索美拉唑)研究中使用)来克服,从而增加T细胞癌症免疫疗法的临床潜力。

 

这是一个令人兴奋的靶向治疗的新领域: 靶向微环境酸中毒,如上所示,通过使用质子泵抑制剂(PPIs),以减少或逆转促进肿瘤生成、肿瘤侵袭和肿瘤恶化的微环境酸化。

 

突破导致转移性疾病

我们现在终于有人类临床数据证实这种方法:上海癌症中心的研究人员在中国和在意大利罗马的国立卫生研究院在2012年的SABCS 大会上展示了一个随机试验的结果-这个实验调查了在乳腺癌转移病人中,在使用esomeprazole (Nexium埃索美拉唑)的同时加上高剂量质子泵抑制剂(PPI)疗法能否改善化疗效果。

 

他们发现,对比没有使用PPI疗法的普通乳腺癌转移患者,PPI疗法显著延长了无进展生存期。

更富戏剧性的是,在哪些恶性程度越高、预后最差的转移性乳腺癌即三阴乳腺癌(TNBC)患者,PPI疗法的使用比没有使用者,无进展生存期几乎延长了三倍。

 

这些是突破性的发现,如果在III期试验结果进一步获得证实,表示二个:

(1)    一个独一无二的无毒干预能改善转移性肿瘤的生存结果;

(2)    癌症新陈代谢假说的重要确认,特别是在晚期癌症微环境酸中毒作为潜在的治疗目标;

 

 [:我期望在即将到来的SABCS 2013年会议上有进一步的确认]

 

 

 

Why does cancer have an acidic microenvironment?

 

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?

_____________________________________________________

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.

 

Why does cancer have an acidic microenvironment?  https://www.researchgate.net/post/Why_does_cancer_have_an_acidic_microenvironment