📚 Cancer: Cellular and Molecular Mechanisms | 癌症发生的细胞与分子机制
Cancer is not a single disease but a collection of related diseases characterised by uncontrolled cell division, evasion of normal growth control, and the ability to invade other tissues. Understanding the cellular and molecular mechanisms underlying cancer is fundamental to A-Level Biology, as it integrates knowledge of the cell cycle, gene expression, DNA repair, and the immune system.
癌症并非单一疾病，而是一类相关疾病的统称，其特征是细胞不受控制地分裂、逃避正常的生长调控，并具备侵入其他组织的能力。理解癌症发生的细胞与分子机制是A-Level生物学的核心内容，它整合了细胞周期、基因表达、DNA修复和免疫系统等多方面知识。
1. What Is Cancer? | 什么是癌症？
Cancer arises when a single cell accumulates multiple mutations in genes that control cell division, apoptosis, and DNA repair. These mutations give the cell a selective growth advantage, allowing it to proliferate abnormally and form a tumour. Tumours may be benign, remaining localised and encapsulated, or malignant, invading surrounding tissues and spreading to distant sites.
癌症源于单个细胞在控制细胞分裂、细胞凋亡和DNA修复的基因中累积了多个突变。这些突变赋予细胞选择性生长优势，使其异常增殖并形成肿瘤。肿瘤可分为良性——保持局限并具有包膜，以及恶性——侵入周围组织并扩散至远处部位。
All cancers are ultimately genetic diseases, but the genetic changes involved are not necessarily inherited. They arise from mutations in somatic cells, caused by environmental factors, replication errors, or inherited predispositions. Importantly, cancer development is a multi-step process, typically requiring 4–10 distinct mutations to accumulate over many years.
所有癌症本质上都是遗传疾病，但涉及的基因改变不一定来自遗传。这些改变源于体细胞中的突变，由环境因素、复制错误或遗传易感性引起。重要的是，癌症发生是一个多步骤过程，通常需要4-10个不同突变在多年间逐步累积。
2. The Cell Cycle and Its Regulation | 细胞周期及其调控
The cell cycle consists of four phases: G₁ (gap 1), S (DNA synthesis), G₂ (gap 2), and M (mitosis). Progression through these phases is controlled by cyclin-dependent kinases (CDKs), which are activated by binding to cyclin proteins. The levels of cyclins fluctuate throughout the cycle, ensuring that each phase is completed before the next begins.
细胞周期包含四个阶段：G₁期（第一间隙期）、S期（DNA合成期）、G₂期（第二间隙期）和M期（有丝分裂期）。细胞周期通过依赖细胞周期蛋白的激酶（CDK）进行调控，CDK通过与细胞周期蛋白结合而被激活。细胞周期蛋白的水平在整个周期中波动，确保每个阶段完成后才进入下一阶段。
Key checkpoints exist at G₁/S, G₂/M, and during M phase. The G₁/S checkpoint, also called the restriction point in mammalian cells, is particularly important: if conditions are unfavourable — such as DNA damage or insufficient nutrients — the cell exits the cycle into G₀ (quiescence) or undergoes apoptosis. Cancer cells often lose these checkpoint controls, allowing them to divide even under adverse conditions.
在G₁/S、G₂/M以及M期过程中存在关键的检查点。G₁/S检查点（在哺乳动物细胞中也称为限制点）尤为重要：如果条件不利——例如存在DNA损伤或营养不足——细胞将退出周期进入G₀期（静止期）或发生凋亡。癌细胞常常丢失这些检查点控制，使其即使在不利条件下也能持续分裂。
Cyclin-CDK complex → phosphorylates target proteins → cell cycle progression
3. Proto-oncogenes and Oncogenes | 原癌基因与癌基因
Proto-oncogenes are normal genes that promote cell division or cell survival. They encode proteins such as growth factors, growth factor receptors, signal transduction molecules, and transcription factors. When mutated or overexpressed, proto-oncogenes become oncogenes — cancer-causing genes that drive excessive proliferation.
原癌基因是促进细胞分裂或细胞存活的正常基因。它们编码生长因子、生长因子受体、信号转导分子和转录因子等蛋白质。当发生突变或过度表达时，原癌基因转变为癌基因——即驱动过度增殖的致癌基因。
The conversion of a proto-oncogene to an oncogene can occur through several mechanisms. A point mutation may produce a hyperactive protein, a process called gain-of-function mutation. Gene amplification increases the copy number, leading to protein overexpression. A chromosomal translocation can place the gene under the control of a constitutively active promoter, as seen in the Philadelphia chromosome in chronic myeloid leukaemia.
原癌基因转变为癌基因可通过多种机制发生。点突变可能产生过度活跃的蛋白质，这一过程称为功能获得性突变。基因扩增增加拷贝数，导致蛋白质过表达。染色体易位可将基因置于持续活跃启动子的控制之下，如慢性髓性白血病中的费城染色体。
Because oncogenes exert a dominant effect, a single mutated allele is sufficient to contribute to cancer. Classic examples include RAS, which encodes a GTPase involved in growth factor signalling, and MYC, a transcription factor that regulates genes involved in cell proliferation. Mutations in RAS are found in approximately 30% of all human tumours.
由于癌基因具有显性效应，单个突变等位基因即足以促进癌症发生。经典例子包括RAS——编码参与生长因子信号传导的GTP酶，以及MYC——调控细胞增殖相关基因的转录因子。RAS突变存在于约30%的人类肿瘤中。
4. Tumour Suppressor Genes | 肿瘤抑制基因
Tumour suppressor genes encode proteins that inhibit cell division, promote DNA repair, or trigger apoptosis. Unlike oncogenes, tumour suppressor genes are recessive at the cellular level: both alleles must be inactivated — often through two separate “hits” — for the protective function to be lost. This is known as Knudson’s two-hit hypothesis.
肿瘤抑制基因编码抑制细胞分裂、促进DNA修复或触发凋亡的蛋白质。与癌基因不同，肿瘤抑制基因在细胞水平上是隐性的：两个等位基因都必须失活——通常通过两次独立的”打击”——保护功能才会丧失。这就是Knudson的二次打击假说。
The TP53 gene, encoding the p53 protein, is the most frequently mutated tumour suppressor gene in human cancers, found altered in over 50% of tumours. p53 acts as “the guardian of the genome”: it detects DNA damage, arrests the cell cycle at the G₁/S checkpoint, and activates DNA repair enzymes. If the damage is irreparable, p53 triggers apoptosis. Loss of p53 function therefore allows damaged cells to survive and accumulate further mutations.
TP53基因编码p53蛋白，是人类癌症中最常发生突变的肿瘤抑制基因，在超过50%的肿瘤中发生改变。p53被称为”基因组卫士”：它能检测DNA损伤，将细胞周期阻滞在G₁/S检查点，并激活DNA修复酶。如果损伤无法修复，p53会触发细胞凋亡。因此，p53功能的丧失使受损细胞得以存活并累积更多突变。
Another important tumour suppressor is the retinoblastoma protein (Rb), encoded by the RB1 gene. Rb controls the G₁/S checkpoint by binding to the transcription factor E2F. When Rb is phosphorylated by cyclin-CDK complexes, E2F is released to activate S-phase genes. Inactivating mutations in RB1 abolish this brake on cell division.
另一个重要的肿瘤抑制因子是视网膜母细胞瘤蛋白（Rb），由RB1基因编码。Rb通过结合转录因子E2F控制G₁/S检查点。当Rb被细胞周期蛋白-CDK复合物磷酸化后，E2F被释放以激活S期基因。RB1的失活突变消除了这一细胞分裂的”刹车”。
5. Mutagens, Carcinogens and DNA Damage | 诱变剂、致癌物与DNA损伤
Mutagens are agents that increase the frequency of mutations, while carcinogens are mutagens that specifically cause cancer. They include physical agents such as ionising radiation (X-rays, γ-rays) and ultraviolet (UV) light; chemical agents such as tobacco smoke components, aflatoxin, and benzene; and biological agents such as certain viruses, including HPV (human papillomavirus) and hepatitis B virus.
诱变剂是增加突变频率的因子，而致癌物是特异性地导致癌症的诱变剂。它们包括物理因子，如电离辐射（X射线、γ射线）和紫外线；化学因子，如烟草烟雾成分、黄曲霉毒素和苯；以及生物因子，如某些病毒，包括人乳头瘤病毒（HPV）和乙型肝炎病毒。
Ionising radiation causes double-strand breaks in DNA, while UV light induces thymine dimers. Both types of damage, if not repaired, lead to mutations. Chemical carcinogens often form DNA adducts — bulky chemical groups covalently bound to DNA bases — which distort the double helix and cause replication errors. Many chemical carcinogens are metabolically activated in the liver by cytochrome P450 enzymes into highly reactive electrophiles.
电离辐射导致DNA双链断裂，而紫外线诱导胸腺嘧啶二聚体。这两种损伤如果未被修复，都会导致突变。化学致癌物通常形成DNA加合物——共价结合到DNA碱基上的大体积化学基团——这会扭曲双螺旋结构并引起复制错误。许多化学致癌物在肝脏中由细胞色素P450酶代谢活化为高反应性的亲电子物质。
Cells possess multiple DNA repair systems, including base excision repair (BER), nucleotide excision repair (NER), and homologous recombination for double-strand breaks. Hereditary defects in these systems greatly increase cancer risk. For example, mutations in BRCA1 and BRCA2, which function in homologous recombination repair, predispose women to breast and ovarian cancer.
细胞拥有多种DNA修复系统，包括碱基切除修复（BER）、核苷酸切除修复（NER）以及针对双链断裂的同源重组修复。这些系统的遗传性缺陷大大增加癌症风险。例如，BRCA1和BRCA2突变在同源重组修复中发挥作用，使女性易患乳腺癌和卵巢癌。
6. Apoptosis and Its Evasion | 细胞凋亡及其逃逸
Apoptosis, or programmed cell death, is an energy-dependent process of controlled cell suicide. It is essential for development, tissue homeostasis, and the elimination of damaged cells. Apoptotic cells shrink, their chromatin condenses, the plasma membrane blebs, and DNA is fragmented; the cell ultimately breaks into apoptotic bodies that are phagocytosed by neighbouring cells or macrophages.
细胞凋亡，即程序性细胞死亡，是一种依赖能量的受控细胞自杀过程。它对发育、组织稳态和清除受损细胞至关重要。凋亡细胞收缩、染色质凝聚、质膜出泡、DNA片段化；细胞最终碎裂为凋亡小体，被邻近细胞或巨噬细胞吞噬。
Two major pathways trigger apoptosis: the extrinsic pathway, activated by death ligands binding to cell-surface receptors (e.g., Fas ligand binding to Fas), and the intrinsic pathway, triggered by intracellular stress such as DNA damage. Both pathways converge on caspases — a family of cysteine proteases — which execute the cell death programme.
两条主要通路触发细胞凋亡：外源性通路，由死亡配体结合细胞表面受体（如Fas配体结合Fas）激活；内源性通路，由DNA损伤等细胞内应激触发。两条通路汇聚于胱天蛋白酶——一个半胱氨酸蛋白酶家族——由其执行细胞死亡程序。
Cancer cells frequently evade apoptosis. Overexpression of anti-apoptotic proteins such as Bcl-2, or loss of pro-apoptotic proteins such as Bax, allows damaged cells to survive. Mutations that inactivate p53 also remove the apoptosis trigger. This evasion is a hallmark of cancer, enabling cells with dangerous mutations to persist and expand clonally.
癌细胞经常逃逸细胞凋亡。抗凋亡蛋白（如Bcl-2）的过度表达，或促凋亡蛋白（如Bax）的缺失，使受损细胞得以存活。使p53失活的突变也移除了凋亡触发机制。这种逃逸是癌症的一个标志，使携带危险突变的细胞能够持续存在并克隆扩增。
7. Angiogenesis and Metastasis | 血管生成与转移
For a tumour to grow beyond approximately 1–2 mm in diameter, it must establish a blood supply through angiogenesis. Cancer cells secrete vascular endothelial growth factor (VEGF) and other pro-angiogenic factors, which stimulate the sprouting of new capillaries from existing vessels. The new blood supply delivers oxygen and nutrients and removes waste products, while also providing a route for metastasis.
肿瘤要生长到大约1-2毫米直径以上，必须通过血管生成建立血液供应。癌细胞分泌血管内皮生长因子（VEGF）和其他促血管生成因子，刺激现有血管萌发新的毛细血管。新的血液供应输送氧气和营养物并清除代谢废物，同时也为转移提供了途径。
Metastasis is the spread of cancer cells from the primary tumour to distant organs. It involves a sequence of steps: invasion of surrounding tissue, intravasation into blood or lymphatic vessels, survival in the circulation, extravasation at a distant site, and colonisation to form secondary tumours. This cascade requires cancer cells to degrade the extracellular matrix using matrix metalloproteinases (MMPs) and to alter their adhesion properties.
转移是癌细胞从原发肿瘤扩散到远处器官的过程。它涉及一系列步骤：侵入周围组织、进入血液或淋巴管（内渗）、在循环中存活、在远处部位穿出血管（外渗）、以及定植形成继发肿瘤。这一级联过程要求癌细胞利用基质金属蛋白酶（MMPs）降解细胞外基质，并改变其粘附特性。
A key change in metastatic cells is reduced expression of E-cadherin, a cell adhesion molecule. Loss of E-cadherin weakens cell-cell adhesion, enabling detachment from the primary tumour. This phenomenon, known as the epithelial-mesenchymal transition (EMT), is a critical early step in metastasis and is regulated by transcription factors such as Snail and Twist.
转移细胞的一个关键变化是E-钙粘蛋白（一种细胞粘附分子）表达减少。E-钙粘蛋白的缺失削弱了细胞间粘附，使细胞能够从原发肿瘤脱离。这一现象称为上皮-间质转化（EMT），是转移的关键早期步骤，由Snail和Twist等转录因子调控。
8. Genetic Predisposition | 遗传易感性
Most cancers are sporadic, arising from somatic mutations accumulated during a person’s lifetime. However, about 5–10% of cancers show clear hereditary predisposition. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) are classic examples, each caused by inherited mutations in specific genes.
大多数癌症是散发性的，源于个体一生中累积的体细胞突变。然而，约5-10%的癌症表现出明显的遗传易感性。家族性腺瘤性息肉病（FAP）和遗传性非息肉病性结直肠癌（HNPCC）是典型例子，分别由特定基因的遗传突变引起。
In FAP, an inherited mutation in the APC gene predisposes individuals to develop hundreds of polyps in the colon, some of which inevitably progress to cancer. The APC protein is part of a destruction complex that targets β-catenin for degradation; when APC is mutated, β-catenin accumulates and activates genes promoting cell proliferation.
在FAP中，APC基因的遗传突变使个体易发结肠中成百上千的息肉，其中一些不可避免地进展为癌症。APC蛋白是靶向β-连环蛋白降解的破坏复合物的一部分；当APC发生突变时，β-连环蛋白累积并激活促进细胞增殖的基因。
It is important to note that inherited mutations typically confer a predisposition, not certainty. They provide the “first hit” in Knudson’s model, greatly increasing the probability that a second somatic mutation will complete the inactivation of a tumour suppressor gene. This explains why hereditary cancers tend to occur at earlier ages and often bilaterally in paired organs.
需要注意的是，遗传突变通常赋予的是易感性而非必然性。它们提供了Knudson模型中的”第一次打击”，大大增加了第二次体细胞突变完成肿瘤抑制基因失活的概率。这解释了为什么遗传性癌症往往发病年龄更早，且常在成对器官中双侧发生。
9. Cancer Treatment and Prevention | 癌症的治疗与预防
Understanding the molecular mechanisms of cancer has revolutionised treatment. Conventional chemotherapy targets rapidly dividing cells by interfering with DNA synthesis or mitosis. For example, cisplatin crosslinks DNA strands, while taxanes stabilise microtubules and block mitotic spindle function. However, these drugs also affect normal dividing cells, causing side effects such as hair loss and immunosuppression.
理解癌症的分子机制已经彻底改变了治疗方法。传统化疗通过干扰DNA合成或有丝分裂来靶向快速分裂的细胞。例如，顺铂使DNA链交联，而紫杉烷类稳定微管并阻断有丝分裂纺锤体功能。然而，这些药物也会影响正常分裂细胞，引起脱发和免疫抑制等副作用。
Targeted therapies exploit specific molecular differences between cancer and normal cells. Trastuzumab (Herceptin) is a monoclonal antibody against the HER2 receptor, which is overexpressed in some breast cancers. Imatinib (Gleevec) inhibits the BCR-ABL tyrosine kinase created by the Philadelphia chromosome translocation in chronic myeloid leukaemia. PARP inhibitors selectively kill cancer cells with BRCA mutations by exploiting synthetic lethality.
靶向治疗利用癌细胞与正常细胞之间的特定分子差异。曲妥珠单抗（赫赛汀）是针对HER2受体的单克隆抗体，该受体在某些乳腺癌中过度表达。伊马替尼（格列卫）抑制慢性髓性白血病中由费城染色体易位产生的BCR-ABL酪氨酸激酶。PARP抑制剂通过利用合成致死性选择性杀死携带BRCA突变的癌细胞。
Immunotherapy has emerged as a powerful approach. Immune checkpoint inhibitors, such as anti-PD-1 antibodies, block the interaction between PD-1 on T cells and PD-L1 on cancer cells, thereby reactivating the immune system to attack the tumour. Cancer vaccines, such as the HPV vaccine, prevent infection by oncogenic viruses and thus prevent the associated cancers.
免疫治疗已成为一种强效方法。免疫检查点抑制剂，如抗PD-1抗体，阻断T细胞上PD-1与癌细胞上PD-L1之间的相互作用，从而重新激活免疫系统攻击肿瘤。癌症疫苗，如HPV疫苗，预防致癌病毒感染，从而预防相关癌症。
10. Conclusion | 结论
Cancer arises from the accumulation of genetic and epigenetic alterations that disrupt the finely balanced control of cell division, apoptosis, and genome maintenance. Proto-oncogenes become hyperactive oncogenes, tumour suppressor genes are inactivated, and cells acquire the ability to evade apoptosis, sustain angiogenesis, and metastasise. These mechanisms are not isolated — they interact in complex networks that vary between cancer types and even between patients.
癌症源于破坏细胞分裂、细胞凋亡和基因组维护精细平衡的遗传和表观遗传改变的累积。原癌基因转变为过度活跃的癌基因，肿瘤抑制基因失活，细胞获得逃逸凋亡、维持血管生成和转移的能力。这些机制并非孤立存在——它们在复杂的网络相互作用，且因癌症类型甚至患者个体而异。
For A-Level Biology, mastering the concepts of cell cycle checkpoints, oncogenes, tumour suppressor genes, and the hallmarks of cancer provides a framework for understanding both the disease process and modern therapeutic strategies. The continued integration of molecular biology into clinical practice promises increasingly effective, personalised approaches to cancer treatment.
对于A-Level生物学而言，掌握细胞周期检查点、癌基因、肿瘤抑制基因和癌症标志物的概念，为理解疾病过程和现代治疗策略提供了框架。分子生物学与临床实践的持续融合，为日益有效和个性化的癌症治疗方法带来了希望。
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