Mechanisms, consequences and regulation of pH non-uniformity in 3-D tissue structures: implications on cancer therapy

我们的目的是研究调节多细胞组织中酸碱平衡（pH）的机制，特别强调肿瘤。活细胞产生酸，这是新陈代谢的最终产物。酸必须排出细胞，到达最近的毛细血管，以维持允许健康细胞功能的细胞内pH值（pHi）。酸的有效排气也是维持多细胞组织均匀pHi的必要条件。这对于灌注不足和代谢活跃的组织尤其重要，例如发展中的肿瘤，其中可变的细胞-毛细血管扩散距离容易导致ph梯度和核心酸度。尽管在分离细胞的ph调节领域取得了重大进展，但在组织水平上运作的综合机制知之甚少。可能对后者起作用的分子包括pH缓冲液、碳酸酐酶、间隙连接通道和酸/碱膜转运蛋白。我们将利用分子生物学、pH成像和计算模型来研究这些机制。这项研究将使用巨大的、三维的癌细胞簇（“球体”）作为肿瘤发展的体外模型。癌症良好的生存前景可能表明，有效的酸排放机制在肿瘤中实施。抑制这些机制可能为治疗癌症提供新的治疗策略。控制细胞内外的pH值也可能影响目前用于化疗的某些弱碱性药物的细胞摄取。

Our aim is to study the mechanisms that regulate the acid/base balance (pH) in multi-cellular tissue, with particular emphasis on tumours.Living cells produce acid, an end-product of metabolism. Acid must be vented out of cells, to the nearest blood capillary, in order to maintain an intracellular pH (pHi) that is permissive for healthy cell function. Efficient venting of acid is also necessary to maintain uniform pHi across multi-cellular tissue. This is particularly critical for under-perfused and metabolically-active tissues, such as developing tumours, where variable cell-to-capillary diffusion distances predispose to pHi-gradients and core-acidity.Although significant progress has been made in the field of pHi-regulation in isolated cells, little is known about the integrated mechanisms that operate at tissue-level. Molecules likely to contribute to the latter include pH buffers, carbonic anhydrase enzymes, gap junction channels and acid/base membrane transporters. We will investigate these mechanisms using molecular biology, pH imaging and computational modelling. The research will use large, three-dimensional clusters (‘spheroids’) of cancer-derived cells as an in vitro model of developing tumours.The good survival prospects of cancer may suggest that efficient mechanisms for venting acid are implemented in tumours. Inhibiting these mechanisms may offer novel therapeutic strategies for treating cancer. Manipulation of pH within and outside cells may also affect the cellular uptake of certain weakly basic drugs that are currently used in chemotherapy.