Neoplasia: Molecular Basis of Cancer PDF

# **Neoplasia: "Molecular Basis of Cancer"** The document describes the molecular basis of cancer, focusing on the characteristics and mechanisms that contribute to its development. ## **Hallmarks of Cancer** The document highlights the **eight fundamental changes in cell physiology** that define...

# **Neoplasia: "Molecular Basis of Cancer"** The document describes the molecular basis of cancer, focusing on the characteristics and mechanisms that contribute to its development. ## **Hallmarks of Cancer** The document highlights the **eight fundamental changes in cell physiology** that define cancer: 1. **Self-sufficiency in growth signals:** Cancer cells become independent of external growth signals and can proliferate autonomously. 2. **Insensitivity to growth-inhibitory signals:** Cancer cells evade signals that normally stop cellular growth, allowing them to proliferate uncontrollably. 3. **Altered cellular metabolism:** Cancer cells reprogram their metabolism to meet their high energy demands, leading to inefficient use of nutrients and a favorable environment for tumor growth. 4. **Evasion of apoptosis:** Cancer cells evade programmed cell death, preventing their elimination by the body. 5. **Limitless replicative potential:** Cancer cells acquire the ability to divide indefinitely, bypassing the normal limit to cell divisions. 6. **Sustained angiogenesis:** Cancer cells induce the formation of new blood vessels to supply the tumor with nutrients and oxygen. 7. **Ability to invade and metastasize:** Cancer cells acquire the capacity to invade surrounding tissues and spread to distant organs. 8. **Ability to evade the host immune response:** Cancer cells can suppress the immune system, evading immune surveillance and destruction. ## **Genetic Basis of Cancer** - **Nonlethal genetic damage (mutation)** lies at the heart of carcinogenesis. These mutations can be caused by environmental exposures, inherited in the germline, or occur spontaneously and randomly. - **Tumor formation** is a process of clonal expansion of a single precursor cell that has incurred genetic damage. - **The principal targets of cancer-causing mutations** are: - Growth-promoting proto-oncogenes - Growth-inhibiting tumor suppressor genes - Genes that regulate programmed cell death (apoptosis) - Genes involved in DNA repair ## **Development of Cancer** Cancer development is a **stepwise acquisition of complementary mutations**. These changes accumulate over time, leading to the transformation of a normal cell into a cancerous one. ### **Phases of Cancer Development** - **Initiating mutation:** The first mutation introduces a change that predisposes the cell to further alterations. - **Acquisition of genomic instability:** Cells become increasingly vulnerable to mutations due to defects in DNA repair mechanisms. - **Acquisition of cancer hallmarks:** The accumulation of mutations results in the development of the key characteristics of cancer. - **Further genetic evolution:** The tumor continues to acquire mutations, leading to diverse subclones and increased heterogeneity. - **Diagnosis:** Cancer is detectable when the tumor has reached a significant size or spread to other tissues. ## **Cellular and Molecular Hallmarks of Cancer** - **Self-sufficiency in growth signals:** These signals are governed by oncogenes, genes that promote autonomous cell growth. The normal cellular counterparts are **proto-oncogenes**. ### **Oncogenes and Proto-oncogenes** - **Protooncogenes** are **physiologic regulators** of cell proliferation and differentiation. - **Oncogenes** are characterized by the **ability to promote cell growth in the absence of normal mitogenic stimulus**. - **Oncoproteins** are the **products of oncogenes**, resembling the normal products of proto-oncogenes. However, they are devoid of important regulatory elements. ### **Functional Categories of Oncogenes** - **Growth factors:** Contribute to cell proliferation. - **Growth factor receptors:** Facilitate signaling pathways triggered by growth factors. - **Proteins involved in signal transduction:** mediate the signal cascade between growth factor receptors and targets. - **Nuclear regulatory proteins:** control gene expression. - **Cell-cycle regulators:** regulate the progression of the cell cycle. ### **Selected Oncogenes** The document provides a table listing specific oncogenes, their mode of activation, and associated human tumors. ## **Growth Factor Signaling Pathways in Cancer** - Growth factor signaling pathways are crucial for controlling cell growth and proliferation. - **Oncoproteins**, such as growth factor receptors, RAS, PI3K, MYC, and D-cyclins, can get activated by mutations in various cancers. - **GAPs (GTPase-activating proteins)** act as brakes on RAS activation, while **PTEN (phosphatase and tensin homolog)** serves the same function for PI3K. ## **Growth Factors** - Normal cells require stimulation by growth factors to proliferate. - Cancer cells synthesize their own growth factors, creating an **autocrine loop** that promotes uncontrolled growth. - **Glioblastomas** exhibit this phenomenon, expressing both platelet-derived growth factor (PDGF) and the PDGF receptor tyrosine kinases. ## **Growth Factor Receptors** - **Receptor tyrosine kinases** are essential for signaling pathways in cancer. - **Oncogenic versions** of these receptors are associated with mutations that lead to constitutive, growth factor-independent tyrosine kinase activity. - Examples include: - **ERBB1:** Encodes the epidermal growth factor receptor (EGFR) and is associated with lung adenocarcinomas. - **ERBB2:** Amplified in certain breast carcinomas, leading to overexpression of the HER2 receptor and constitutive tyrosine kinase activity. - **ALK:** Activated by gene rearrangement and is associated with certain cancers, such as lung adenocarcinoma and lymphomas. ## **Downstream Components of the Receptor Tyrosine Kinase Signaling Pathway** - **RAS mutations** are frequent in human tumors, affecting 15-20% of all human cancers. - **RAS** is normally activated by receptors to exchange GDP for GTP. - **GAPs** regulate RAS activity, but **mutant forms of RAS** bind GAP but fail to exhibit proper GTPase activity, leading to sustained signaling. ## **Oncogenic BRAF and PI3K Mutations** - **BRAF** is a serine/threonine protein kinase, and activating mutations in BRAF stimulate downstream kinases and activate transcription factors. - **PI3K mutations** affect the catalytic subunits and lead to increased enzyme activity. ## **Alterations in Nonreceptor Tyrosine Kinases** - In **chronic myelogenous leukemia (CML)** and some acute lymphoblastic leukemias, the **ABL gene** is translocated from chromosome 9 to chromosome 22, where it fuses with the **BCR gene**. - This fusion creates a **constitutively active, oncogenic BCR-ABL tyrosine kinase**. ## **Transcription Factors** - Signal transduction pathways converge on the nucleus, where the expression of target genes takes place. - **Transcription factors** of this class include the products of MYC, MYB, JUN, FOS, and REL proto-oncogenes. - **MYC** is particularly important in human tumors and acts as a **master regulator of cell growth**. ## **Cyclins and Cyclin-Dependent Kinases** - The progression of cells through the cell cycle is controlled by **cyclin-dependent kinases (CDKs)** and **cyclins**. - These complexes phosphorylate target proteins, driving cells through the cell cycle. - The document discusses **two main cell cycle checkpoints**: G1/S transition and G2/M transition. - These checkpoints are regulated by a balance of growth-promoting and growth-suppressing factors, as well as by sensors of DNA damage. ## **Tumor Suppressor Genes** - Tumor suppressor genes encode proteins that apply brakes to cell proliferation. - **Abnormalities in these genes** lead to a failure of growth inhibition. - **Tumor suppressor proteins** form a network of checkpoints that prevent uncontrolled growth. - Key tumor suppressor proteins include **RB (retinoblastoma protein)** and **p53**. - **RB** regulates the G1-S checkpoint of the cell cycle. - **p53** acts as a **guardian of the genome**, regulating cell cycle progression, DNA repair, senescence, and apoptosis. ## **TP53: Guardian of the Genome** - **TP53** is the most frequently mutated gene in human cancers. - **Loss-of-function mutations** in TP53 are found in over 50% of cancers. - **Individuals inheriting a mutated TP53 allele** are at a higher risk of developing cancer (Li-Fraumeni syndrome). - **p53** is normally undetectable in normal cells. - In stressed cells, p53 is released from the inhibitory effects of MDM2, a key regulator of its stability. - **DNA damage and hypoxia** are key initiators of p53 activation. - Once activated, **p53** opposes neoplastic transformation by inducing either **transient cell cycle arrest**, **senescence**, or **programmed cell death (apoptosis)**. ## **APC: Gatekeeper of Colonic Neoplasia** - **Adenomatous polyposis coli (APC)** is a tumor suppressor gene that downregulates growth promoting signaling pathways. - **Germline loss-of-function mutations** in APC are associated with **familial adenomatous polyposis** (FAP), an autosomal dominant disorder characterized by the development of thousands of adenomatous polyps in the colon. - **Malignant transformation** of these polyps leads to colon cancer. The document provides a comprehensive overview of key molecular processes involved in cancer development. It emphasizes the significance of understanding these mechanisms for the development of effective cancer therapies.