Heme,含铁的四吡咯,在几乎所有生物体中都是必不可少的。血红素生物合成需要精确调节,特别是考虑到原卟啉IX的潜在细胞毒性,血红素形成之前的中间。这里,我们报道了卟啉中间体在肿瘤微环境(TME)中的积累,我们认为这是血红素生物合成失调的结果,伴随着对中期基因的癌症生存依赖性增强,我们最近称之为“卟啉Overdrive”的过程。具体来说,卟啉在TME的肺癌细胞和基质细胞中积累。在TME的基质细胞内,有证据支持癌症相关成纤维细胞(CAFs)通过不平衡途径积极产生卟啉.相反,正常组织没有卟啉积累,被剥夺肿瘤的CAF停止卟啉过量生产,这表明癌症和肿瘤基质卟啉过度产生都局限于癌症特异性组织生态位。我们的发现的临床相关性是通过建立不平衡的卟啉产生与更具侵袭性的癌症的总体较差生存率之间的相关性来暗示的。这些发现阐明了特别是在肿瘤微环境中的异常卟啉动力学,提示治疗干预的潜在目标。
Heme, an iron-containing tetrapyrrole, is essential in almost all organisms. Heme biosynthesis needs to be precisely regulated particularly given the potential cytotoxicity of protoporphyrin IX, the intermediate preceding heme formation. Here, we report on the
porphyrin intermediate accumulation within the tumor microenvironment (TME), which we propose to result from dysregulation of heme biosynthesis concomitant with an enhanced cancer survival dependence on mid-step genes, a process we recently termed \"Porphyrin Overdrive\". Specifically, porphyrins build up in both lung cancer cells and stromal cells in the TME. Within the TME\'s stromal cells, evidence supports cancer-associated fibroblasts (CAFs) actively producing porphyrins through an imbalanced pathway. Conversely, normal tissues exhibit no
porphyrin accumulation, and CAFs deprived of tumor cease
porphyrin overproduction, indicating that both cancer and tumor-stromal
porphyrin overproduction is confined to the cancer-specific tissue niche. The clinical relevance of our findings is implied by establishing a correlation between imbalanced
porphyrin production and overall poorer survival in more aggressive cancers. These findings illuminate the anomalous
porphyrin dynamics specifically within the tumor microenvironment, suggesting a potential target for therapeutic intervention.