Cancer and Uncontrollable Cell Growth and Death (BSC)

Flashcards covering key vocabulary terms related to cancer, cell growth, cell death, genetic and epigenetic changes, tumor progression, DNA repair mechanisms, and therapeutic targets from the BSC: Cancer and Uncontrollable Cell Growth and Death lecture.

Neoplasia

New Growth.

Neoplasm (Tumor)

An abnormal mass or growth which is uncoordinated with normal tissue, requiring genetic changes for unregulated proliferation.

Benign Tumor

A small tumor without the possibility of metastasis.

Malignant Tumor

Cancers that can invade and destroy adjacent tissues, metastasize, and cause death.

Primary Tumor

Arises from cell division in a single abnormal cell that experienced some heritable change (genetic or epigenetic).

Genomic Instability (in cancer)

Cancer cells accumulate genetic changes at an abnormal rate, giving them a selective advantage.

Epigenetic Changes (in cancer)

Cells contain more heterochromatin, leading to silencing of genes that block tumor progression or are involved in epigenetic modifications.

Viruses (in cancer)

Thought to cause 15% of human cancers, often DNA viruses, responsible for one step in tumor progression (direct or indirect modulation).

Transformation (viral)

When RNA retroviruses insert DNA sequences into the host genome, leading to uncontrollable cell division.

Replicative Cell Senescence

Cells permanently stop dividing after a certain number of population doublings.

Telomerase Activity (in cancer cells)

Maintained in cancer cells, allowing them to bypass replicative senescence and continue dividing.

Proto-oncogenes

Genes in which a gain-of-function mutation can drive a cell toward cancer.

Oncogenes

The mutant (overactive or overexpressed) form of a proto-oncogene, exhibiting a dominant, growth-promoting effect.

Tumor Suppressor Genes

Genes in which a loss-of-function mutation can drive a cell toward cancer, generally recessive.

DNA Maintenance Genes

Genes whose mutation results in genomic instability, allowing mutations in other genes during cell division.

Two-Hit Hypothesis

States that two 'hits' (mutations or epigenetic changes) are typically required in a tumor suppressor gene for cancer to develop.

Benzo[a]pyrene

A combustion product of tobacco smoke that forms bulky lesions in DNA, needing NER for repair.

Nucleotide Excision Repair (NER)

A multienzyme complex that repairs bulky DNA lesions by scanning for double helix distortion, cleaving the backbone, removing the damaged strand, and synthesizing new DNA.

UV-induced DNA Dimers

Formed between adjacent pyrimidines (cytosine or thymine) due to UVB exposure, a common cause of skin cancer.

Base Excision Repair (BER)

Repairs spontaneous small DNA lesions using DNA glycosylases to remove damaged bases, followed by AP endonuclease, DNA polymerase, and DNA ligase.

Ras (proto-oncogene)

A signal-transducing protein, where point mutations (especially in GTP hydrolysis) are common oncogene-inducing mutations, leading to continuous growth signals.

Myc (transcription factor)

A transcription factor that is rapidly induced when cells receive a division signal; mutations (translocations, amplifications) can lead to increased cell motility, telomerase expression, and changes in metabolism.

Bcl2 (gene family)

Controls the release of cytochrome C from mitochondria, with pro-apoptotic proteins (BH123, Bak, Bax) and anti-apoptotic proteins (Bcl2, Bcl-Xl).

Rb (Retinoblastoma gene)

A ubiquitously expressed nuclear phosphoprotein and universal regulator of the cell cycle; when active, it suppresses S-phase gene expression. Inherited mutation in one allele is common in retinoblastoma.

Li-Fraumeni Syndrome

A syndrome characterized by a 25-fold greater chance of developing malignant tumors before age 50, due to an inherited mutation in one p53 allele.

p53 (tumor suppressor)

A gene/protein mutated in nearly all cancers; typically affects its ability to bind DNA and induce p21 transcription, leading to cell cycle arrest.

DNA Damage Checkpoints

Mechanisms that stop the cell cycle if DNA damage is detected (at G1 to S, S slowdown, S to M).

ATM Protein

A kinase that generates intracellular signals in response to spontaneous DNA damage, phosphorylating targets like p53 and Chk1/Chk2 to induce cell cycle arrest.

Loss of p53 (dangers)

Allows cells with DNA damage to progress through the cell cycle, escape apoptosis, divide with damaged chromosomes, and develop resistance to chemotherapy.

APC (Adenomatous Polyposis Coli)

A tumor suppressor gene mutated in Familial Adenomatous Polyposis (FAP), involved in the Wnt pathway as part of a complex that binds "beta"-catenin.

Wnt Pathway (in cancer)

Ligand binding inhibits APC complex proteins, allowing eta-catenin to enter the nucleus and become a transcription factor; implicated in colon cancer when APC is mutated.

Adenoma-Carcinoma Sequence

The progression from a benign adenoma (glandular tumor) to a malignant carcinoma (epithelial cancer), often initiated by APC mutation in sporadic colon tumors.

Hallmarks of Metastasis

Autonomous growth/replication, insensitivity to anti-growth signals, evasion of apoptosis, induction of new blood vessels, invasion, and metastasis.

Angiogenic Switch

The process by which tumors induce new blood vessel formation, often triggered by hypoxia.

VHL (tumor suppressor)

A tumor suppressor protein that, when mutated, can contribute to the angiogenic switch by stabilizing Hif-1.

Hif-1 (proto-oncogene)

A proto-oncogene that induces VEGF and is stabilized in hypoxic conditions, promoting angiogenesis.

VEGF (proto-oncogene)

A proto-oncogene induced by Hif-1, promoting the growth of new blood vessels (angiogenesis).

Tumor Microenvironment

Consists of diverse cell types including cancer cells and stroma, where cross-talk and proteolytic enzymes contribute to ECM remodeling and tumor growth.

Tumor Angiogenesis

The process of new capillary growth converging upon a tumor, which is required for significant tumor cell population increase after initial tumor 'take'.

Nonneovascularized Tumors

Small tumors (normally cubic millimeters), often inhibited by oxygen diffusion limits; can maintain a steady state between cell division and apoptosis, and are generally not metastatic.

Neovascularizing Primary Tumor

Develops an 'angiogenic phenotype' often after malignant transformation, involving a two-way paracrine exchange between tumor cells (secreting angiogenic proteins) and endothelial cells (secreting chemoattractants, mitogens).

Warburg Effect

Describes how cancer cells in hypoxic solid tumors increase anaerobic glycolysis, a selective advantage often due to oncogene activation, tumor suppressor loss, or Hif-1 stabilization.

Induced Vessels (in tumors)

Irregular, tortuous, heterogenous, and leaky due to abnormal signaling, leading to further tissue hypoxia and selecting for more malignant mutant cells.

Inhibition of Angiogenesis (drugs)

Therapeutic strategies targeting new blood vessel formation, either directly or indirectly, using biologics.

What is neoplasia and the fundamental nature of a neoplasm (tumor)?

Neoplasia refers to "New Growth." A neoplasm, or tumor, is an abnormal mass or growth which is uncoordinated with normal tissue, requiring genetic and/or epigenetic changes for unregulated proliferation. A primary tumor arises from cell division in a single abnormal cell that experienced some heritable change.

How do genomic instability and epigenetic changes contribute to cancer development?

Genomic instability means cancer cells accumulate genetic changes at an abnormal rate, giving them a selective advantage. Epigenetic changes involve cells containing more heterochromatin, leading to silencing of genes that block tumor progression or are involved in epigenetic modifications.

What role do viruses play in cancer development?

Viruses are thought to cause 15\% of human cancers, often DNA viruses, responsible for one step in tumor progression (direct or indirect modulation). Viral transformation occurs when RNA retroviruses insert DNA sequences into the host genome, leading to uncontrollable cell division.

How do cancer cells overcome replicative cell senescence?

Normal cells undergo replicative cell senescence, where they permanently stop dividing after a certain number of population doublings. Cancer cells bypass this by maintaining telomerase activity, which allows them to continue dividing indefinitely.

How do you differentiate a benign tumor from a malignant tumor?

A benign tumor is a small tumor without the possibility of metastasis. A malignant tumor (cancer) can invade and destroy adjacent tissues, metastasize to distant sites, and cause death.

Differentiate between proto-oncogenes, oncogenes, and tumor suppressor genes.

Proto-oncogenes are normal genes in which a gain-of-function mutation can drive a cell toward cancer. Oncogenes are the mutant (overactive or overexpressed) form of a proto-oncogene, exhibiting a dominant, growth-promoting effect. Tumor suppressor genes are genes in which a loss-of-function mutation can drive a cell toward cancer, generally recessive.

Explain the Two-Hit Hypothesis.

The Two-Hit Hypothesis states that two 'hits' (mutations or epigenetic changes) are typically required to inactivate both alleles of a tumor suppressor gene for cancer to develop.

What is the role of the Ras proto-oncogene in cancer initiation and progression?

Ras is a signal-transducing protein. Point mutations in Ras (especially in GTP hydrolysis) are common oncogene-inducing mutations, leading to continuous growth signals and uncontrolled cell proliferation, thus contributing to tumor initiation.

How does Myc transcription factor dysfunction contribute to tumor progression?

Myc is a transcription factor rapidly induced when cells receive a division signal. Mutations in Myc (e.g., translocations, amplifications) can lead to increased cell motility, telomerase expression, and changes in metabolism, all promoting tumor progression.

Describe the function of the Bcl2 gene family and its contribution to tumor progression.

The Bcl2 gene family controls the release of cytochrome C from mitochondria. It includes pro-apoptotic proteins (e.g., BH123, Bak, Bax) and anti-apoptotic proteins (e.g., Bcl2, Bcl-Xl). Dysregulation, such as overexpression of anti-apoptotic proteins, allows cancer cells to evade programmed cell death and continue proliferating, contributing directly to tumor progression.

What is the significance of the Rb (Retinoblastoma gene) as a cell cycle regulator?

Rb is a ubiquitously expressed nuclear phosphoprotein and universal regulator of the cell cycle. When active, it suppresses S-phase gene expression, preventing uncontrolled cell division. An inherited mutation in one allele is common in retinoblastoma.

Why is p53 considered a critical tumor suppressor, and what are the dangers of its loss?

p53 is a tumor suppressor gene/protein mutated in nearly all cancers. It typically affects its ability to bind DNA and induce p21 transcription, leading to cell cycle arrest. Loss of p53 is dangerous because it allows cells with DNA damage to progress through the cell cycle, escape apoptosis, divide with damaged chromosomes, and develop resistance to chemotherapy, thereby promoting tumor progression.

How do VHL, Hif-1, and VEGF genes contribute to tumor angiogenesis?

VHL is a tumor suppressor protein that, when mutated, fails to degrade Hif-1. Hif-1 is a proto-oncogene stabilized in hypoxic conditions, and it induces VEGF. VEGF is a proto-oncogene that promotes the growth of new blood vessels (angiogenesis), which is critical for tumor progression.

What is the overall role of DNA repair mechanisms in cancer prevention?

DNA repair mechanisms prevent cancer by correcting genetic mutations and damage that can lead to oncogene activation or tumor suppressor gene inactivation, thereby maintaining genomic stability and preventing uncontrolled cell proliferation.

Describe Nucleotide Excision Repair (NER).

NER is a multienzyme complex that repairs bulky DNA lesions (e.g., caused by Benzo[a]pyrene, a combustion product of tobacco smoke, or UV-induced DNA Dimers) by scanning for double helix distortion, cleaving the backbone, removing the damaged strand, and synthesizing new DNA.

Describe Base Excision Repair (BER).

BER repairs spontaneous small DNA lesions using DNA glycosylases to remove damaged bases, followed by AP endonuclease, DNA polymerase, and DNA ligase to restore the correct sequence.

How do DNA damage checkpoints and the ATM protein contribute to cancer prevention?

DNA damage checkpoints are mechanisms that stop the cell cycle (at G1 to S, S slowdown, S to M) if DNA damage is detected. The ATM protein is a kinase that generates intracellular signals in response to spontaneous DNA damage, phosphorylating targets like p53 and Chk1/Chk2 to induce cell cycle arrest and allow for DNA repair, thus preventing cancer.

How do case studies like Li-Fraumeni Syndrome and Familial Adenomatous Polyposis (FAP) help in understanding cancer mechanisms?

These case studies (Li-Fraumeni involving p53 and FAP involving APC) clearly illustrate direct links between specific inherited gene mutations and subsequent cancer development. They demonstrate concepts such as the 'two-hit hypothesis' and the progressive accumulation of genetic changes (e.g., the Adenoma-Carcinoma Sequence) that drive malignancy.

Explain the Adenoma-Carcinoma Sequence in colon cancer, including the role of the APC gene and Wnt Pathway.

The Adenoma-Carcinoma Sequence describes the progression from a benign adenoma (glandular tumor) to a malignant carcinoma (epithelial cancer), often initiated by mutations in the APC (Adenomatous Polyposis Coli) tumor suppressor gene in sporadic colon tumors. In the Wnt Pathway, normal APC is part of a complex that binds to and facilitates the degradation of \beta-catenin; mutated APC leads to elevated \beta-catenin levels, which enters the nucleus to act as a transcription factor promoting uncontrolled cell growth.

What are the hallmarks of metastasis?

The hallmarks of metastasis include autonomous growth/replication, insensitivity to anti-growth signals, evasion of apoptosis, induction of new blood vessels, invasion, and metastasis.

Explain tumor angiogenesis and the angiogenic switch.

Tumor angiogenesis is the process of new capillary growth converging upon a tumor, which is required for significant tumor cell population increase after initial tumor 'take'. The angiogenic switch is the process by which tumors induce new blood vessel formation, often triggered by hypoxia, allowing a nonneovascularized tumor to become a neovascularizing primary tumor. These induced vessels are typically irregular, tortuous, heterogenous, and leaky.