Hallmarks of Cancer
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What is meant by sustained proliferative signaling in cancer cells?

Sustained proliferative signaling refers to cancer cells' ability to continuously stimulate their own growth by deregulating growth-promoting signals.

How do somatic mutations contribute to the evasion of growth suppressors in cancer?

Somatic mutations can inactivate tumor suppressor genes like RB and TP53, which regulate cell growth and division, allowing cancer cells to grow uncontrollably.

What is the role of RAS mutations in sustaining proliferative signaling?

RAS mutations disrupt the GTPase activity of Ras, leading to disrupted negative-feedback mechanisms that normally regulate cell growth.

Identify two ways cancer cells can achieve autocrine proliferative signaling.

<p>Cancer cells can achieve autocrine signaling through the production of their own growth factors and by elevated levels of receptor proteins, making them hyper-responsive.</p> Signup and view all the answers

Explain the impact of tumor-promoting inflammation on cancer development.

<p>Tumor-promoting inflammation can create a supportive microenvironment that facilitates tumor growth and progression by providing signals that promote malignancy.</p> Signup and view all the answers

What role do the retinoblastoma-associated (RB) and TP53 genes play in cancer development?

<p>RB integrates signals to progress the cell cycle, while TP53 regulates genes for growth arrest and apoptosis.</p> Signup and view all the answers

How do tumor cells avoid programmed cell death?

<p>Tumor cells avoid apoptosis by inactivating TP53 and increasing antiapoptotic regulators like Bcl-2.</p> Signup and view all the answers

What is the significance of telomerase activation in cancer cells?

<p>Telomerase activation maintains telomere length, enabling unlimited cell division and aiding in DNA repair.</p> Signup and view all the answers

Describe the process of angiogenesis in tumor progression.

<p>Angiogenesis involves the continuous formation of new blood vessels, regulated by factors like VEGF-A.</p> Signup and view all the answers

What is the epithelial-mesenchymal transition (EMT) and its role in cancer invasion?

<p>EMT is a process where epithelial cells acquire migratory properties, leading to increased invasion and metastasis.</p> Signup and view all the answers

How does the Warburg effect relate to cancer cell metabolism?

<p>The Warburg effect describes cancer cells preferentially using aerobic glycolysis for energy even in the presence of oxygen.</p> Signup and view all the answers

What genetic factors contribute to genome instability in cancers?

<p>Mutations in DNA repair genes, such as BRCA1, contribute to genomic instability and chromosomal instability (CIN).</p> Signup and view all the answers

In what way does the tumor microenvironment (TME) contribute to immune evasion?

<p>The TME produces immunosuppressive factors such as TGF-β, inhibiting immune responses against the tumor.</p> Signup and view all the answers

Explain the significance of E-cadherin loss in tumor progression.

<p>Loss of E-cadherin disrupts contact inhibition, allowing cells to continue proliferating and promotes EMT.</p> Signup and view all the answers

What role do inflammatory cells play in tumor-promoting inflammation?

<p>Inflammatory cells provide growth factors and create a pro-tumor environment, supporting cancer progression.</p> Signup and view all the answers

How does necrosis differ from apoptosis in cancer?

<p>Necrosis is an uncontrolled cell death response that triggers inflammation, while apoptosis is a regulated process.</p> Signup and view all the answers

What is the role of transcription factors like Snail and Twist in EMT?

<p>Transcription factors like Snail and Twist inhibit E-cadherin expression, initiating EMT and enhancing tumor cell motility.</p> Signup and view all the answers

What factors influence the angiogenic switch during tumor progression?

<p>The angiogenic switch is influenced by the balance between pro-angiogenic factors like VEGF and anti-angiogenic factors like TSP-1.</p> Signup and view all the answers

Describe the importance of autophagy in cancer cells.

<p>Autophagy helps cancer cells survive under stress and contributes to resistance against cell death.</p> Signup and view all the answers

What role do BRCA1 and BRCA2 mutations play in hereditary breast cancer?

<p>BRCA1 and BRCA2 mutations are autosomal dominant tumor suppressor genes that maintain DNA integrity and significantly increase the risk of breast and other cancers.</p> Signup and view all the answers

How does the age of pregnancy influence breast cancer risk?

<p>Having no children (nulliparity) or having children later in life increases breast cancer risk as pregnancy promotes terminal differentiation in breast tissue.</p> Signup and view all the answers

What is the difference between ductal carcinoma in situ (DCIS) and invasive breast cancer?

<p>DCIS is a non-invasive condition where malignant cells are confined to the ducts, while invasive breast cancer involves the invasion of malignant cells into surrounding stroma.</p> Signup and view all the answers

Explain the significance of breast density in relation to breast cancer risk.

<p>Radiologically dense breasts are associated with a higher risk of breast cancer due to the increased difficulty in detecting tumors and potential biological factors.</p> Signup and view all the answers

What is the impact of atypical hyperplasia on breast cancer risk?

<p>Atypical hyperplasia presents a moderate increased risk of breast cancer, increasing the likelihood by 4-5 times compared to individuals without this condition.</p> Signup and view all the answers

How does cumulative estrogen exposure contribute to breast cancer risk?

<p>Longer cumulative estrogen exposure from factors like early menarche, late menopause, and obesity significantly increases the risk of developing breast cancer.</p> Signup and view all the answers

Identify two conditions classified as benign lesions that do not increase breast cancer risk.

<p>Conditions such as fibrocystic changes and fibroadenomas are benign lesions that do not increase breast cancer risk.</p> Signup and view all the answers

What association does radiation exposure have with breast cancer risk?

<p>Previous radiation exposure, particularly to the chest area, is associated with an increased risk of developing breast cancer later in life.</p> Signup and view all the answers

What are the distinguishing histopathological features of Ductal Carcinoma In Situ (DCIS)?

<p>Malignant cells with variable growth patterns and necrosis, commonly associated with calcifications.</p> Signup and view all the answers

How does Lobular Carcinoma In Situ (LCIS) differ from DCIS in terms of future cancer risk?

<p>LCIS is a non-obligate precursor with a bilateral risk of lobular type breast cancer, as opposed to being a direct precursor like DCIS.</p> Signup and view all the answers

What clinical features suggest the presence of Invasive Breast Cancer (IBC)?

<p>Discrete lumps, pain, nipple changes, and skin alterations like peau d'orange.</p> Signup and view all the answers

Explain the significance of having clear surgical margins in breast cancer treatment.

<p>Clear surgical margins reduce the risk of local recurrence and indicate complete removal of the tumor.</p> Signup and view all the answers

What role do estrogen and progesterone receptor status play in breast cancer prognosis?

<p>Positive receptor status indicates a better response to hormone therapy and generally correlates with a more favorable prognosis.</p> Signup and view all the answers

What are the four distinct subtypes of breast cancer identified through molecular profiling?

<p>Luminal A, Luminal B, HER2 enriched, and Basal-like.</p> Signup and view all the answers

Describe the treatment options available for a patient with ER-positive breast cancer.

<p>Treatment may include hormonal therapy, surgical excision, and possibly radiation therapy.</p> Signup and view all the answers

What imaging modalities are typically used in the workup of suspected invasive breast cancer?

<p>Mammography (MMG), ultrasound (US), and magnetic resonance imaging (MRI).</p> Signup and view all the answers

What is the primary goal of adjuvant radiotherapy in breast cancer treatment?

<p>To reduce the risk of recurrence after surgical excision.</p> Signup and view all the answers

How is Invasive Ductal Carcinoma (IDC) commonly classified?

<p>IDC is classified based on type, grade, stage, and biomarker expression.</p> Signup and view all the answers

What does it mean if a breast cancer tumor is classified as HER2 positive?

<p>It indicates the tumor has an overexpression of the HER2 protein, often making it more aggressive but treatable with targeted therapies.</p> Signup and view all the answers

What are the implications of necrosis observed in histopathological examinations of breast cancer?

<p>Necrosis may indicate aggressive tumor behavior and can affect prognostic assessments.</p> Signup and view all the answers

What is the significance of the Nottingham grading system for breast cancer?

<p>It assesses tumor differentiation and growth rate, providing important prognostic information.</p> Signup and view all the answers

How can the presence of paget's disease of the nipple be assessed histopathologically?

<p>The presence of breast cancer cells alongside keratinocytes in the nipple epidermis indicates paget's disease.</p> Signup and view all the answers

Explain the importance of monitoring and managing Lobular Carcinoma In Situ (LCIS).

<p>LCIS requires increased surveillance due to its association with a higher risk of developing invasive cancer in either breast.</p> Signup and view all the answers

Study Notes

Hallmarks of Cancer

  • Cancer cells continuously promote their own growth by manipulating growth signals.
  • Mutations and disrupted feedback mechanisms like RAS mutations contribute to this.
  • Ways to sustain proliferative signaling:
    • Autocrine proliferative signaling: Cancer cells produce and respond to their own growth factors.
    • Signaling to normal cells: Cancer cells signal to surrounding cells in the tumor microenvironment (stroma).
    • Increased receptors: Cancer cells have more receptors than normal cells, making them hyper-responsive to growth factors.
    • GF independence: Cancer cells can bypass the need for growth factors through continuous activation of downstream signaling pathways.
    • Somatic mutations: Additional downstream pathways are activated by mutations, leading to uncontrolled proliferation.
    • Disrupted negative feedback mechanisms: Mutations can affect proteins like Ras GTPase, disrupting normal feedback control and causing uncontrolled growth.

Evading Growth Suppressors

  • Inactivation of tumor suppressor genes (TSGs) like RB and TP53 allows unregulated cell growth.
  • RB protein: Integrates signals from inside and outside the cell to regulate the cell cycle.
  • TP53 protein: Known as the "guardian of the genome," it plays a crucial role in cell cycle arrest, apoptosis, senescence, autophagy, and metabolic changes within the cell.

Resisting Cell Death

  • Cancer cells evade apoptosis by:
    • Loss of TP53 function: Mutations in TP53 disrupt its ability to induce cell death.
    • Increased antiapoptotic regulators: Cancer cells increase expression of proteins like Bcl-2 and Bcl-xl, which prevent apoptosis.
    • Downregulation of proapoptotic factors: Cancer cells decrease the expression of proteins like Bax, Bim, and Puma, which promote apoptosis.
    • Short-circuiting death pathways: Cancer cells can interrupt the programmed cell death process initiated by external signals.

Enabling Replicative Immortality

  • Telomerase activation in cancer cells maintains telomere length, allowing unlimited cell division.
  • Telomerase (TERT) also enhances cell proliferation, resistance to apoptosis, and participates in DNA repair.

Inducing Angiogenesis

  • Angiogenesis, the formation of new blood vessels, sustains tumor growth by providing nutrients and oxygen.
  • VEGF-A: A pro-angiogenic factor that promotes blood vessel formation.
  • TSP-1: An anti-angiogenic factor that inhibits blood vessel growth.
  • Angiogenic switch: In cancer, the angiogenic switch is always "on," leading to abnormal blood vessel formation with distorted structure, erratic blood flow, and leakage.

Activating Invasion and Metastasis

  • Invasion and metastasis are multi-step processes:

    • Local invasion: Cancer cells spread from their original location.
    • Intravasation: Cancer cells enter the bloodstream or lymphatic system.
    • Extravasation: Cancer cells exit the bloodstream or lymphatic system.
    • Micro-metastases: Small clusters of cancer cells form at distant sites.
    • Colonization: Cancer cells establish a new tumor at a distant site.

  • Epithelial-Mesenchymal Transition (EMT): Cancer cells undergo EMT to become more mobile and invasive.

    • Loss of E-cadherin: A key event in EMT, E-cadherin is a protein that normally prevents cell proliferation when cells are tightly packed.
    • Transcription factors: Transcription factors like Snail, Slug, Twist, and Zeb1/2 initiate EMT by inhibiting E-cadherin expression and promoting cell motility and invasiveness.

Deregulating Cellular Metabolism

  • Cancer cells exhibit the Warburg effect, using aerobic glycolysis to produce energy even in the presence of oxygen.
  • This shift facilitates rapid growth and is influenced by oncogenes like RAS and MYC and TSGs like TP53.
  • Increased glucose transporters (GLUT1) on the cell surface enhance glucose uptake.
  • Hypoxia and transcription factors: Low oxygen levels and transcription factors like HIF1α and HIF2α regulate glucose transporter expression.

Avoiding Immune Destruction

  • Cancer cells evade immune destruction by creating an immunosuppressive tumor microenvironment (TME).
  • TGF-β: A cytokine that suppresses immune responses and contributes to the immunosuppressive TME.

Enabling Characteristics

  • Genome instability and mutation: Cancer cells have a high rate of mutations, due to errors in DNA replication and repair.

    • Chromosomal instability (CIN): A common type of genomic instability where chromosomes are lost or duplicated, altering gene expression.
    • Mutations in DNA repair genes: Mutations in DNA repair genes like BRCA1 increase the frequency of mutations.

  • Tumor-promoting inflammation: Chronic inflammation in the tumor environment promotes cancer progression by providing growth factors and aiding metastasis.

    • Immune suppression: Inflammatory cells contribute to an immunosuppressive environment, allowing cancer cells to evade the immune response.
    • Pro-tumor environment: Inflammation promotes tumor growth by supplying growth factors and survival factors.
    • Crosstalk: Immune cells and cancer cells interact through inflammatory mediators, further promoting tumor growth.

Risk Factors of Breast Cancer

  • Gender and Age: Women are significantly more likely to develop breast cancer than men. The risk increases with age.
  • Previous Breast Cancer: Having had breast cancer in one breast increases the risk of developing it in the other breast.
  • Estrogen Exposure: Longer exposure to estrogen increases breast cancer risk. This includes factors like early menarche (first period), late menopause, obesity, and the use of contraceptives.
  • Pregnancy: Never having been pregnant (nulliparity) or having a first pregnancy later in life increases the risk. Pregnancy induces terminal differentiation in breast tissue, reducing cancer risk.
  • Genetics: Family history of breast cancer increases the risk. Specific gene mutations, like BRCA1 and BRCA2, significantly increase the risk of developing breast cancer.
  • Breast Density: Radiologically dense breasts, which appear white on mammograms, are associated with a higher risk of breast cancer.
  • Radiation Exposure: Previous radiation exposure, particularly to the chest area, increases the risk of breast cancer.

Hereditary Breast Cancer

  • Early Onset & Bilateral: Hereditary breast cancer tends to occur at a younger age and may affect both breasts.
  • BRCA1/BRCA2 Mutations: These genes act as tumor suppressor genes, responsible for maintaining DNA integrity. Mutations in these genes lead to increased cancer risk.
  • Autosomal Dominant Inheritance: BRCA1/BRCA2 mutations follow an autosomal dominant inheritance pattern, meaning one copy of the mutated gene is sufficient to increase cancer risk.
  • Other Cancer Risks: Mutations in BRCA1/BRCA2 increase the risk of other cancers, including ovarian, colon, prostate, pancreatic, esophageal, and male breast cancers.
  • Other Syndromes: Other genetic syndromes, such as Li-Fraumeni (P53 mutation) and Cowden's disease (PTEN), are also associated with increased breast cancer risk.

Pathology of Breast Cancer

Benign Lesions

  • Non-proliferative and many proliferative breast diseases have no increased breast cancer risk. These include inflammatory conditions, fibrocystic changes, adenosis, PASH, and fibroadenoma.
  • Some proliferative conditions do have an increased risk of breast cancer. The magnitude of risk depends on the degree of histological atypia. These conditions include usual hyperplasia, complex sclerosing lesion/radial scar, and papilloma.

Proliferative Breast Diseases

  • Without Atypia: These conditions are associated with a mild increase in breast cancer risk. Categories include epithelial hyperplasia, columnar cell change, intraductal papilloma, and complex sclerosing lesion/radial scar.
  • With Atypia: These conditions are associated with a moderate (4-5 times) increased risk of breast cancer. These categories include atypical papilloma, columnar cell change with atypia ('flat epithelial atypia'), and atypical hyperplasia ('Atypical ductal hyperplasia' or 'atypical lobular hyperplasia').

In Situ Breast Cancer

  • Malignant cells are confined to the ductal-lobular system without invading the basement membrane into stroma.
  • Although non-invasive, in situ breast cancer presents a high risk of progression to invasive breast cancer.
  • Classification:
    • Ductal Carcinoma In Situ (DCIS): Non-invasive, confined to ducts (often lobular).
    • Lobular Carcinoma In Situ (LCIS): Confined within lobular spaces, occasionally duct spaces.

Ductal Carcinoma In Situ (DCIS)

  • Non-invasive: Confined to the ducts (often lobular). If left untreated, it can become invasive.
  • High risk of invasive breast cancer.
  • Curable: Because it is non-invasive, there is no metastatic potential.
  • Clinical Manifestations: Often presents as calcifications on mammograms, or as background findings in biopsies taken for invasive breast cancer.
  • Histopathology: Characterized by malignant cells with varying growth patterns (solid, cribriform, micropapillary etc.), necrosis, and calcifications.
  • Grading: Classified by the grade of nuclear atypia: low, intermediate, or high.
  • Management: Surgical excision with clear margins, often followed by radiotherapy.
  • Prognosis: The prognosis for DCIS depends on the grade, extent of the lesion, and the completeness of excision.

Paget's Nipple

  • Rare form of breast cancer: Breast cancer cells spread to the epidermis of the nipple.
  • Associated with high-grade DCIS: Spread occurs through the lactiferous ducts.
  • Clinical Manifestations: Characterized by a red, weeping, or "eczematous" nipple.
  • Histopathology: Breast cancer cells are mixed with keratinocytes in the epidermis, with DCIS in the lactiferous ducts.
  • Management: Surgical excision with clear margins to remove the associated DCIS (+/- invasive).
  • Prognosis: Dependent on the features of the associated DCIS (+/- invasive).

Lobular Carcinoma In Situ (LCIS)

  • Can be bilateral: May increase the risk of invasive cancer in both breasts.
  • Less well-defined: Compared to DCIS, the cells are less clearly malignant.
  • High risk of lobular breast cancer: At the same site as the LCIS.
  • Similar morphologic features and genetic alterations: Similar to invasive lobular breast cancers.
  • Management:
    • Isolated in core biopsy: Increased surveillance.
    • Associated with high-risk lesions: Management depends on the specific high-risk lesion.
    • In surgical margins during excision: No further action is generally required. Anti-estrogen therapy may be considered.
    • Bilateral mastectomy is not recommended for LCIS alone.

Invasive Breast Cancer

  • Invasion of malignant epithelial cells beyond the myoepithelial layer/basement membrane into the stroma: Leads to metastasis.

  • Clinical Manifestations:

    • Distinct mass (lump) or lumpiness.
    • Pain.
    • Nipple changes or discharge.
    • Skin changes (tethering, peau d'orange, ulceration etc.).
    • Other manifestations, including distant metastasis.

  • Workup:

    • Examination: Of the breast, axilla, and overall health.
    • Pathology: Fine needle aspiration or core biopsy to identify malignant cells invading the stroma.
    • Classification: Classified in terms of type, grade, stage (degree of spread), biomarker expression, and +/- molecular profile.
    • Prognostic Factors: Predict disease-free survival or overall survival.
    • Predictive Factors: Predict the response to specific treatments.
    • Radiology: Mammograms, ultrasound, and MRI.

    Types of Invasive Cancer

    • Invasive Ductal Carcinoma (IDC): Represents approximately 80% of cases. The most common type, 'no special type' (NST) is the most prevalent.
    • Invasive Lobular Carcinoma (ILC): Makes up about 10% of cases.
    • Special Types: Mucinous, Tubular, micropapillary, and others. These are less common and can have different prognoses.

    Staging

    • Nottingham Grading System: Higher stages predict worse prognosis.
    • AJCC System: A widely used system for staging breast cancer based on the extent of the tumor, spread to lymph nodes, and distant metastasis.

Prognostic and Biomarkers

  • Prognostic Factors: Biological characteristics that predict the course of the disease and survival.
  • Predictive Factors: Characteristics that predict the response to specific treatments.
  • Common Markers:
    • ER/PR: Estrogen receptor (ER) and progesterone receptor (PR) positivity. - Indicates a better response to hormone therapy. - ER+/PR+ breast cancers tend to have a better prognosis than ER-/PR- breast cancers.
    • HER2/neu: Human epidermal growth factor receptor 2 (HER2/neu) positivity. - Often associated with more aggressive breast cancer. - Can be targeted by specific therapies, such as trastuzumab. - HER2/neu is a transmembrane tyrosine kinase (TK) protein that promotes proliferation and invasiveness.

Molecular Profiling

  • Subsets: Identifies four distinct breast cancer subtypes: Luminal A, Luminal B, HER2 enriched, and Basal-like.
  • Prognostic and Predictive Significance: Used to guide treatment decisions.
  • Practical Considerations: Genome-wide expression profiling is not practical for routine use.

Breast Cancer Treatment

  • Surgical Options: Lumpectomy (removal of the tumor and surrounding tissue) or mastectomy (removal of the entire breast) depending on the extent of the cancer.

  • Surgical Management:

    • Surgical excision with clear margins: Mastectomy or wide local excision (WLE).
    • +/- Axillary surgery: Sentinel lymph node biopsy, followed by axillary clearance if the sentinel node is positive.
    • +/- Radiotherapy:
      • To the chest wall: If WLE, 'locally advanced disease,' or positive margins on mastectomy.
      • To the axilla or supraclavicular nodes: If high nodal burden (>4 involved).
    • +/- Chemotherapy: For cases with a high risk of recurrence based on clinical and pathological features.

    Other Treatment Modalities

    • Radiotherapy: Frequently used after surgery to reduce the risk of recurrence.
    • Hormonal Therapy: Used for ER/PR-positive tumors.
    • Chemotherapy and Targeted Therapy: Used for HER2-positive and high-risk cases.

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This quiz delves into the key characteristics of cancer cells, focusing on their ability to promote continuous growth through various mechanisms. Learn about autocrine signaling, receptor overexpression, and how mutations play a crucial role in cancer progression. Test your knowledge on the intricate signaling pathways involved in sustaining proliferative signaling.

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