Kaleem Mohammed, Azmi Lubna, Shahzad Naiyer, Taha Murtada, Kumar Shiv, Mujtaba Md Ali, Hazazi Abdulaziz Ali H, Kayali Asaad
Department of Pharmacology, Dadasaheb Balpande College of Pharmacy, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, India.
Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Science, University of Lucknow, Uttar Pradesh, Lucknow, India.
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 13. doi: 10.1007/s00210-025-04217-5.
Cancer progression is governed by a dynamic interplay of genetic, epigenetic, and molecular mechanisms that regulate tumor initiation, growth, metastasis, and therapy resistance. This review highlights key molecular pathways involved in oncogenesis, focusing on genetic alterations (mutations, amplifications, and translocations) in oncogenes (RAS and MYC) and tumor suppressor genes (TP53 and PTEN). Additionally, genomic instability, resulting from defective DNA repair mechanisms like mismatch repair and homologous recombination (HR), is identified as a critical factor contributing to tumor heterogeneity and clonal evolution. Epigenetic modifications, including DNA methylation, histone acetylation, and non-coding RNA regulation, further remodel chromatin structure and modulate gene expression, influencing tumor initiation, growth, metastasis, and response to treatment. Post-translational modifications, such as the attachment of a Small Ubiquitin-like Modifier (SUMO) to a target protein and ubiquitination, further influence autophagy, apoptosis, and cellular plasticity, enabling cancer cells to survive therapeutic stress. Cutting-edge technologies such as CRISPR-Cas9-mediated epigenome editing and single-cell RNA sequencing have opened new doors to understanding cellular diversity and regulatory networks in cancer. The review further examines the tumor microenvironment, including stromal remodeling, immune evasion, and hypoxia-driven signaling pathways, which are critical modulators of tumor progression and drug resistance to treatment. By integrating molecular, genetic, and epigenetic perspectives, this study underscores the crucial need for innovative, targeted therapeutic approaches to address the complexity and adaptability of cancer, thereby paving the way for more effective treatments.
癌症进展受遗传、表观遗传和分子机制的动态相互作用支配，这些机制调节肿瘤的起始、生长、转移和治疗抗性。本综述重点介绍了肿瘤发生过程中涉及的关键分子途径，着重探讨了癌基因（RAS和MYC）和肿瘤抑制基因（TP53和PTEN）中的遗传改变（突变、扩增和易位）。此外，由错配修复和同源重组（HR）等有缺陷的DNA修复机制导致的基因组不稳定，被确定为促成肿瘤异质性和克隆进化的关键因素。表观遗传修饰，包括DNA甲基化、组蛋白乙酰化和非编码RNA调控，进一步重塑染色质结构并调节基因表达，影响肿瘤的起始、生长、转移和对治疗的反应。翻译后修饰，如小泛素样修饰物（SUMO）与靶蛋白的附着以及泛素化，进一步影响自噬、凋亡和细胞可塑性，使癌细胞能够在治疗压力下存活。CRISPR-Cas9介导的表观基因组编辑和单细胞RNA测序等前沿技术为理解癌症中的细胞多样性和调控网络打开了新的大门。该综述进一步研究了肿瘤微环境，包括基质重塑、免疫逃逸和缺氧驱动的信号通路，这些都是肿瘤进展和治疗耐药性的关键调节因子。通过整合分子、遗传和表观遗传观点，本研究强调了创新的靶向治疗方法对于应对癌症的复杂性和适应性的迫切需求，从而为更有效的治疗铺平道路。
