Week 11 - Cancer Growth, Regulation, and Treatment

Questions and Answers

What is the primary reason why tumors require angiogenesis?

To induce apoptosis in surrounding tissues

To stimulate the growth of inflammatory cells

To deliver oxygen and nutrients to the tumor cells (correct)

To remove nutrients from the surrounding blood vessels

What characterizes blood vessels in growing cancers?

They are highly branched and complex

They are absent and non-functional

They are abnormal and leaky (correct)

They are normal and functional

What is the role of endothelial cells in tumor growth?

They induce apoptosis in tumor cells

They secrete growth factors and contribute to tumor growth (correct)

They inhibit tumor growth

They are neutral and do not affect tumor growth

What is the result of leaky blood vessels in tumors?

Increased access of cancer cells to distant transport Signup and view all the answers

What controls angiogenesis in tumors?

A balance between angiogenesis promoters and inhibitors Signup and view all the answers

Who are the producers of angiogenesis activators?

Tumor cells, inflammatory cells, and other stromal cells Signup and view all the answers

What can release proangiogenic basic fibroblast growth factors (bFGF) stored in the ECM?

Proteases from tumor cells or stromal cells Signup and view all the answers

How are angiogenesis inhibitors produced?

By proteolytic cleavage of plasminogen and collagen Signup and view all the answers

What is the zone that represents the maximal distance across which oxygen, nutrients, and waste can diffuse from blood vessels?

1- to 2-mm zone Signup and view all the answers

What happens to tumors that do not induce angiogenesis early in their development?

They remain small or in situ, possibly for years Signup and view all the answers

What is the result of a 'gain-of-function' mutation in a signaling pathway?

The proto-oncogene is converted to an oncogene. Signup and view all the answers

Which of the following proteins is an example of an oncoprotein that promotes cell growth?

RAS Signup and view all the answers

What is the normal function of CDKIs?

To inhibit cell growth Signup and view all the answers

What is the result of a loss-of-function mutation in a CDKI?

Cell growth is promoted. Signup and view all the answers

What is the name of the protein resulting from the translocation of the ABL gene in CML?

BCR-ABL Signup and view all the answers

What is the normal function of proto-oncogenes?

To promote cell growth Signup and view all the answers

Which hallmark of cancer refers to cancer cells' ability to grow without external signals?

Self-sufficiency in growth signals Signup and view all the answers

What mechanism allows cancer cells to avoid programmed cell death?

Evasion of apoptosis Signup and view all the answers

Which hallmark of cancer involves increased blood vessel formation to supply nutrients to tumors?

Sustained angiogenesis Signup and view all the answers

How do cancer cells typically behave towards their surrounding cellular environment?

Profit from resources while evading control Signup and view all the answers

What characteristic of cancer cells allows them to persist and multiply despite systemic challenges?

Evasion of immune surveillance Signup and view all the answers

What is a consequence of genomic instability in cancer cells?

Higher likelihood of mutations and adaptations Signup and view all the answers

Which statement regarding tumor suppressor genes is true?

They inhibit cell cycle progression. Signup and view all the answers

What is the primary function of the retinoblastoma gene (RB)?

To block transcription of S phase genes. Signup and view all the answers

Which of the following cancers is NOT commonly associated with biallelic loss of the retinoblastoma gene (RB)?

Prostate cancer Signup and view all the answers

Why is the TP53 gene often referred to as the 'guardian of the genome'?

It plays a role in apoptosis and DNA repair. Signup and view all the answers

What percentage of human cancers feature defects in the TP53 gene?

More than 70% Signup and view all the answers

In what way does a mutation in the retinoblastoma gene (RB) affect its function?

It decreases its efficiency in blocking progression. Signup and view all the answers

What comparison do cancer stem cells have to normal stem cells in terms of therapy resistance?

Inherent resistance to conventional therapies Signup and view all the answers

Which factor contributes to genomic instability in cancer cells?

High frequency of DNA replication errors Signup and view all the answers

Which of the following conditions is associated with inherited mutations in DNA repair systems?

Xeroderma pigmentosum Signup and view all the answers

What is a common characteristic of BRCA1 and BRCA2 mutations?

Involvement in DNA repair mechanisms Signup and view all the answers

What aspect of genomic instability is commonly observed in certain carcinomas, such as colon cancer?

Alterations in lengths of short repeats Signup and view all the answers

What characterizes 'fragile sites' within the genome?

Sites that are more prone to breakage during replication Signup and view all the answers

What is the primary function of p53 protein when DNA damage occurs?

Induce apoptosis or senescence if DNA repair fails Signup and view all the answers

Which of the following is a consequence of p53 mutation or inhibition?

Uncontrolled cell proliferation Signup and view all the answers

What is the role of E6 protein from high-risk human papillomaviruses in relation to p53?

It inhibits p53 activity to suppress apoptosis Signup and view all the answers

How does loss of cell-cell contact contribute to cell proliferation?

It releases β-catenin into the nucleus, stimulating proliferation genes Signup and view all the answers

Which of the following is NOT a direct consequence of p53 activation?

Angiogenesis Signup and view all the answers

Which of these is a mechanism by which p53 prevents tumor development?

By inducing cell cycle arrest and DNA repair Signup and view all the answers

What is a common symptom of cancer that can be identified through history taking?

Bleeding or blood in sputum, stool, or urine Signup and view all the answers

What is a diagnostic technique used in the laboratory diagnosis of cancer?

Fine needle aspiration Signup and view all the answers

What is a type of antigen that can be used in the diagnosis of cancer? (MACA)

Tumor-associated antigen Signup and view all the answers

What is an important aspect of treating malignancy?

A well-informed patient is extremely important Signup and view all the answers

What can be observed during the examination of a patient with suspected cancer?

Clubbing of fingers Signup and view all the answers

What is a type of test used in the laboratory diagnosis of cancer? (MACA)

Histological test Signup and view all the answers

Why must a doctor understand carcinogens and factors causing malignancy?

To counsel patients on avoiding them. Signup and view all the answers

What should a Doctor of Chiropractic recognize as potential indicators of neoplasia?

Changes in soft tissue tone, stiffness, and adhesions. Signup and view all the answers

Which locations are identified as common sites of metastasis?

Liver, lung, and brain. Signup and view all the answers

What does an alteration in local tissue tone potentially indicate?

Possible presence of metastasis. Signup and view all the answers

Why is it significant for a Doctor of Chiropractic to recognize lymphatic-rich areas?

Changes may indicate possible neoplasia. Signup and view all the answers

What role does knowledge of malignancy-predisposing conditions play for a doctor?

It helps identify potential risk factors in patients. Signup and view all the answers

What might palpation of alterations in joint areas signify?

Possible association with neoplasia. Signup and view all the answers

How can local tissue tone alterations influence the likelihood of metastasis?

They suggest an increased risk for metastasis. Signup and view all the answers

Which of the following is NOT a primary treatment modality for cancer?

Physical Therapy Signup and view all the answers

Which of the following is an example of an alternative immune stimulation method used in cancer treatment?

Hyperthermia Signup and view all the answers

Which of the following is a type of molecule that can be used to stimulate the immune system in cancer treatment? (MACA)

miRNA Signup and view all the answers

Which of the following is NOT a factor that contributes to spontaneous remission of cancer?

Genetic mutations Signup and view all the answers

What is the primary reason why a doctor of chiropractic should be aware of the signs and symptoms of neoplasia?

To be able to refer patients to appropriate specialists Signup and view all the answers

Which of the following is NOT a potential benefit of knowing about neoplasia for a doctor of chiropractic?

Performing manual adjustments to treat cancer Signup and view all the answers

What is the primary cause of cancer-related morbidity and mortality?

Invasion and metastasis Signup and view all the answers

What is the first step in the process of invasion?

Loosening of cell-cell contacts Signup and view all the answers

What is the name of the enzyme overexpressed in malignant tumors of the breast, colon, and stomach?

Type IV collagenase Signup and view all the answers

What is the result of ECM degradation in invasion?

Release of stored growth factors Signup and view all the answers

What is the consequence of ECM alterations in invasion?

Increased aberrant crosslink and stiffness Signup and view all the answers

Which of the following is NOT a characteristic of tumor cells recognized by the immune system as nonself?

Presence of antigens associated with normal tissue function Signup and view all the answers

What is the primary mechanism of antitumor activity mediated by T cells?

Direct cell-mediated cytotoxicity Signup and view all the answers

Which of the following is TRUE regarding the role of natural killer (NK) cells in antitumor immunity?

NK cells can kill tumor cells without prior sensitization Signup and view all the answers

Which of the following is NOT a factor contributing to the evasion of the immune system by tumor cells?

Increased expression of tumor-associated antigens Signup and view all the answers

What type of immune cells are primarily responsible for the osteolytic nature of bone metastases in breast cancer?

Osteoclasts Signup and view all the answers

Which mechanism allows tumors to evade the immune system through the alteration of antigen expression?

Reduced expression of histocompatibility molecules Signup and view all the answers

What is a direct consequence of chronic inflammation induced by necrosis?

Systemic signs such as fatigue and anemia Signup and view all the answers

Which factor contributes to the immunosuppressive environment in tumors?

Secretion of TGF-β Signup and view all the answers

How do infiltrating leukocytes and stromal cells contribute to tumor growth?

They release factors that promote ECM degradation. Signup and view all the answers

What mechanism is associated with the switch of macrophages to M2 phenotype in tumor environments?

Immunosuppressive factors from tumor cells Signup and view all the answers

What is the role of integrins in tumor cells regarding apoptosis and oncogene stimulation?

Integrins alter responses to avoid apoptosis and stimulate oncogenes. Signup and view all the answers

What is necessary for the movement and migration of cancer cells?

A stiff support matrix along with chemotactic factors. Signup and view all the answers

What happens to tumor cells once they are in circulation?

They are vulnerable to destruction due to various stresses. Signup and view all the answers

What is organ tropism in the context of tumor cells?

The tendency of tumor cells to express chemokine receptors for specific organs. Signup and view all the answers

What factor may contribute to the dormancy of established metastases?

Secretion of cytokines and growth factors by metastatic cells. Signup and view all the answers

Study Notes

Induction and Activation of Nuclear Regulatory Factors

Initiate and regulate DNA transcription and biosynthesis of cellular components for cell division
Include synthesis of ribosomes, organelles, membrane components, and cell cycle regulatory proteins

Autocrine Stimulation and Cell Cycle Progression

Cells produce their own growth factors, such as platelet-derived growth factor (PDGF) and transforming growth factor α (TGF-α)
Stimulate stroma to increase production of growth factors, mostly through PAMP and DAMP signals
Cells can also have receptor "gain-of-function" mutations, leading to over-expression or altered functioning of growth factor receptors

Insensitivity to Growth-Inhibitory Signals

Tumor suppressor genes, such as retinoblastoma gene (RB) and TP53, regulate cell cycle progression and arrest
Loss of function or mutation in these genes can lead to uncontrolled cell growth and division
TP53 is often referred to as the "guardian of the genome"

Evasion of Apoptosis

Apoptosis, or programmed cell death, occurs through extrinsic and intrinsic pathways
Overexpression of anti-apoptotic proteins, such as BCL2, can inhibit apoptosis and promote cancer cell survival
Chemotherapy and radiation therapy kill cancer cells by inducing apoptosis through the intrinsic pathway

Limitless Replicative Potential (Immortality)

Normal cells have a limited replicative potential due to telomere shortening, leading to mitotic crisis and death
Cancer cells often maintain telomere length through telomerase upregulation or alternative mechanisms, allowing for infinite replication
Cancer stem cells, which have self-renewal capabilities, are thought to be present in all types of cancers

Sustained Angiogenesis

Tumors require a blood supply for oxygen and nutrient delivery, as well as waste removal
Tumors stimulate angiogenesis, leading to the formation of new, abnormal blood vessels
Angiogenesis is regulated by a balance of promoters and inhibitors, including factors produced by tumor cells, inflammatory cells, and stromal cells

Hallmarks of Cancer

Self-sufficiency in growth signals
- Growth factor binds to specific membrane receptor
- Activated receptor triggers signal proteins, leading to transmission of signal across cytosol and into the nucleus
- Parallel metabolic changes and correlation with other signals, including mechanical tension, PAMP, and DAMP
- Signaling path "gain-of-function" can convert proto-oncogenes to oncogenes
Insensitivity to growth-inhibitory signals
- Retinoblastoma gene (RB) regulates cell cycle progression and is often lost in various tumors
- TP53 gene regulates cell cycle arrest, DNA repair, and apoptosis in response to DNA damage, hypoxia, and telomere shortening
- Loss of contact inhibition leads to uncontrolled proliferation
Altered cellular metabolism
Evasion of apoptosis
Limitless replicative potential (immortality)
Sustained angiogenesis
Invasion and metastasis
Evasion of immune surveillance
Genomic instability
Tumor-promoting inflammation

Self-Sufficiency in Growth Signals

Growth signals are normally temporary and limited
Activated growth factor receptors lead to gain-of-function mutations, promoting cell growth and proliferation
Examples of oncogenes: RAS (30% of all studied cancers), RAF, PI3K, AKT
BCR-ABL protein in CML responds well to BCR-ABL kinase inhibitors like imatinib

Insensitivity to Growth-Inhibitory Signals

Retinoblastoma gene (RB) is a tumor suppressor gene that regulates cell cycle progression
TP53 gene is a tumor suppressor gene that triggers cell cycle arrest, DNA repair, and apoptosis in response to DNA damage
Loss of contact inhibition leads to uncontrolled proliferation
Cancer stem cells are hard to identify and may arise from normal stem cells or acquired genetic lesions

Genomic Instability

High frequency of mutations within the genome of a cell line
DNA is most vulnerable during replication, and "fragile sites" may exist along exposed chromatin
Inherited mutations of genes involved in DNA repair systems increase the risk of cancer and neurodegenerative diseases
Examples of genes involved in DNA repair: BRCA1, BRCA2, and xeroderma pigmentosum

Diagnosis of Cancer

Exposure to carcinogens such as asbestos, pesticides, and other substances at work, home, or during travel can be a risk factor
Symptoms include unexplained growths, lumps, bleeding, or blood in sputum, stool, or urine
Changes in bowel or bladder habits, visible moles, discharge, hoarseness, indigestion, and difficulty swallowing can also be indicative of cancer
Unusual coughing or other persisting symptoms should be investigated

Examination

Inspection: obvious changes in warts or moles, sores that don't heal, anemia, hypoxia, clubbing nails, and thromboflebitis
Auscultation: listening to lung and abdominal sounds for signs of obstruction
Palpation: feeling for growths, lumps, or changes in tissue firmness, including palpating lymph nodes at joints

Laboratory Diagnosis of Cancer

Histological diagnosis: examination of cytological samples, fine needle aspiration, and biopsy
Biochemical assays: measuring levels of substances like prostate-specific antigen, human chorionic gonadotropin, and catecholamine metabolites
Receptor analysis and tumor antigen tests, including tests for MAGE-1 and other tumor-associated antigens

Treatment of Malignancy

Treatment is not usually an emergency, and patients should be well-informed and keep a journal
Surgery, radiation, chemotherapy, molecular therapies, and alternative immune stimulation may be used
Immune stimulation approaches include PAMP/TLR, hyperthermia, miRNA, and spontaneous remission

Importance for the Doctor of Chiropractic

Recognizing symptoms and signs of neoplasia is essential for early diagnosis and referral
Knowing about carcinogens and factors causing malignancy can help with patient counseling
Understanding conditions that predispose to malignancy can inform patient care
Palpating soft tissue tone alteration, stiffness, and/or adhesions can be a sign of possible neoplasia
Joint areas are lymphatic-rich and may be associated with neoplasia
Liver, lung, and brain are common sites of metastasis, and alterations in local tissue tone may indicate their presence

Invasion and Metastasis

Complex interactions between cancer cells and normal stroma lead to invasion and metastasis, the major causes of cancer-related morbidity and mortality.
Only a few metastases are produced despite millions of cells being released into the circulation each day from a primary tumor.
Invasion occurs in four steps:
- Loosening of cell-cell contacts: inactivation, alterations, or downregulation of epithelial surface proteins and intercellular adhesion molecules (e.g., cadherins).
- Basement membranes and ECM degradation: mediated by proteolytic enzymes (matrix metalloproteases and cathepsins), release of stored growth factors, and reduced concentrations of metalloproteinase inhibitors.
- ECM alterations: fragmented ECM fibers expose different adhesion sites, increased stiffness, and altered integrin response.
- Locomotion/migration: tumor cells attach to the matrix at the leading edge, detach at the trailing edge, and contract the actin cytoskeleton to ratchet forward.

Vascular Dissemination and Homing of Tumor Cells

Many tumors arrest in the first capillary bed they encounter (e.g., lung and liver).
Tumor cells in circulation are vulnerable to destruction (mechanical shear stress, apoptosis, and immune defenses).
Tumor cells tend to aggregate in clumps due to adhesions among tumor cells and between tumor cells and blood cells (particularly platelets).
Some tumors show organ tropism due to expression of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site.

Evading Immunity

Tumor cells can be recognized by the immune system as nonself and destroyed.
Immunosuppressed patients have an increased risk of developing cancer.
Cell proteins presented on the cell surface by MHC class I molecules are recognized by CD8+ CTLs as tumor antigens.
Antitumor activity is mediated by cell-mediated mechanisms, including:
- T-cell mediated cytotoxicity: clear protective role against virus-associated neoplasms.
- Natural killer cell cytotoxicity: capable of destroying tumor cells without prior sensitization.
- Macrophage-mediated cytotoxicity: activated macrophages exhibit cytotoxicity against tumor cells.

Chronic Inflammation

Necrosis induces chronic and extensive inflammation, leading to systemic signs and symptoms (e.g., anemia, fatigue, and cachexia).
Infiltrating leukocytes and activated stromal cells secrete growth factors, cytokines, and proteases that promote angiogenesis, fibroblast proliferation, and collagen deposition.
Stromal cell-cancer cell interactions increase the resistance of cancer cells to chemotherapy.

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Description

This quiz covers the initiation and regulation of DNA transcription, biosynthesis of cellular components, and autocrine stimulation in cell cycle progression.