Cancer Definition and Development

Cancer Definition and Characteristics

• Cancer is characterized by uncontrolled cell growth, invasion of surrounding tissues, and sometimes metastasis to distant body sites.
• Abnormal gene function leads to dysregulation of cell proliferation, differentiation, and cell death, causing abnormal cell growth and tumor formation.

Cancer Research Timeline

• 1971: The National Cancer Act significantly increased funding for cancer research and established the National Cancer Institute.
• Understanding of cancer has shifted from viewing it as a single disease to recognizing its genetic basis and heterogeneity, with advances in molecular biology and genetics improving diagnosis, treatment, and prevention strategies.

Terminology

• Hereditary: Inherited genetic traits passed from parents to offspring.
• Familial: Traits or conditions that tend to occur more frequently in family members than in the general population, possibly due to shared genetic and environmental factors.
• Acquired: Characteristics or conditions developed during an individual's life rather than being inherited.
• Transcription: The process of copying a segment of DNA into RNA.
• Dysregulation: Abnormality or impairment in the regulation of a metabolic, physiological, or biological process.
• Proliferation: The rapid multiplication of cells.

Cell Cycle Regulation

• Cyclins regulate the progression of cells through the cell cycle by activating cyclin-dependent kinases (CDKs).
• Growth factors and their receptors influence signal transduction pathways, promoting cell proliferation, survival, and differentiation.

Carcinogenesis

• Carcinogenesis is the process by which normal cells are transformed into cancer cells, involving genetic mutations and epigenetic alterations that disrupt normal cell regulatory mechanisms.
• Knudson's Two-Hit Hypothesis states that cancer results from the accumulation of two genetic mutations or "hits" in a tumor suppressor gene.

Theories of Carcinogenesis

• Somatic Mutation Theory (SMT): Cancer results from accumulated genetic mutations in somatic cells.
• Tissue Organization Field Theory (TOFT): Cancer is a problem of tissue organization, where the microenvironment and cell interactions play a critical role.
• Multi-Step Nature of Cancer: Cancer involves the accumulation of multiple genetic alterations over time, leading to the progression from normal cells to malignant cancer cells.

Cancer Stem Cell Theories

• Cancer stem cells are a subset of tumor cells with self-renewal and differentiation capabilities, contributing to tumor growth, recurrence, and resistance to treatments.
• Proto-oncogenes promote cell growth and division, and can become oncogenes when mutated. Tumor suppressor genes inhibit cell growth and division, and help prevent cancer.

Mechanisms of Oncogene Activation

• Proto-oncogenes can become oncogenes through mutations, gene amplification, chromosomal translocations, and increased expression.
• Gene amplification of HER2 in breast cancer leads to overexpression of the HER2 protein, driving excessive cell proliferation.

Tumor Suppressor Genes

• Tumor suppressor genes regulate cell cycle progression, promote apoptosis, repair DNA damage, and maintain genomic stability.
• TP53 is involved in DNA repair, apoptosis, and cell cycle regulation, and mutations are associated with a wide range of cancers.

Hallmarks of Cancer

• Cancer cells acquire six biological capabilities: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis.
• Cancer cells sustain growth signaling and evade growth suppressors through mutations in growth factor receptors or downstream signaling pathways, and inactivating tumor suppressor genes or bypassing growth-inhibitory signals.

Resisting Cell Death

• Cancer cells resist apoptosis by upregulating anti-apoptotic proteins or downregulating pro-apoptotic proteins.
• TP53 plays a key role in promoting apoptosis in response to cellular stress, and its mutation can prevent apoptosis.

Enabling Replicative Immortality

• Cancer cells bypass senescence by reactivating telomerase, maintaining telomere length, and avoiding telomere shortening.
• Telomeres protect chromosome ends from degradation, and telomerase extends telomeres, allowing cancer cells to divide indefinitely.

Inducing Angiogenesis

• Angiogenesis provides tumors with oxygen and nutrients necessary for growth, and is regulated by factors like VEGF.
• Factors like hypoxia, oncogene activation, and loss of tumor suppressors can trigger the angiogenic switch.

Activating Invasion and Metastasis

• Changes in cell adhesion molecules like cadherins and integrins facilitate cancer metastasis.
• Tissue invasion and metastasis are critical steps in cancer progression, leading to the spread of cancer to other parts of the body.

Importance of Cancer Genetics in Malignant Haematology

• Genetic mutations and epigenetic changes contribute to malignant haematology by disrupting normal blood cell development.
• Chromosomal rearrangements can create fusion genes, activate oncogenes, or inactivate tumor suppressor genes, driving cancer development.

Laboratory Investigations in Haematological Malignancies

• Laboratory investigations include complete blood count (CBC), bone marrow biopsy, cytogenetics, flow cytometry, molecular testing (PCR, FISH), and immunohistochemistry.
• Samples required for malignant cytogenetics include bone marrow aspirates, peripheral blood, and lymph node biopsies.

Principles of Cell Culture

• Mitogens are used in normal peripheral blood cultures to stimulate cell division for cytogenetic analysis.
• Bone marrow samples naturally contain dividing cells, while leukemic blood samples may require mitogens to stimulate cell division.

Principles of Conventional Cytogenetic Culture

• Blocking cells at the S phase ensures synchronization, allowing for the collection of a high number of metaphase cells for analysis.
• Mitotic arrest is achieved using chemicals like colchicine or colcemid, which inhibit spindle formation and trap cells in metaphase.

Harvesting and Slide Preparation

• Steps involved in preparing slides for cytogenetic analysis include cell culture, harvesting cells, hypotonic treatment, fixation, slide preparation, and staining.
• Temperature and humidity control are important during slide making to prevent artifacts.

The Role of Molecular Haematology

• Molecular haematology identifies genetic mutations and markers, aiding in diagnosis, prognosis, and monitoring treatment response.
• PCR is the most sensitive technique for detecting mutations, followed by FISH and then conventional cytogenetics.

The Role of Clinical Cytogenetics in Haematological Malignancies

• Clinical cytogenetics helps confirm the diagnosis of haematological malignancies by identifying chromosomal abnormalities.
• Stratifying patients based on cytogenetic analysis allows for personalized treatment plans and improves clinical trial design.

Chromosomal Rearrangements

• Types of chromosomal rearrangements commonly observed in haematological malignancies include translocations, inversions, deletions, and duplications.
• Chromosomal translocations can create fusion genes or place oncogenes under the control of strong promoters, leading to their overexpression and oncogenic activity.

FISH Principles

• FISH uses fluorescent probes that bind to specific DNA sequences, allowing for the visualization and localization of genetic abnormalities in cells.
• DNA probes labeled with fluorescent dyes hybridize to complementary sequences in the genome, highlighting specific regions for analysis under a fluorescence microscope.