Molecular Neoplasia Dr. Nelson 5/5/14 Flashcards
Define neoplasia, and state the underlying pathogenic mechanism of neoplasia.
Best definition of neoplasm (from Robbins): “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which invoked the change.”
The underlying pathogenesis of neoplasia is that the stimulus causes genetic alterations in a single cell, which are then passed on to the progeny of the tumor cell and all subsequent tumor cells, allowing excessive and unregulated proliferation that becomes autonomous. Thus a neoplasm is a clonal proliferation, forming a tissue mass that results from excessive and unregulated cell proliferation due to the genetic alterations.
List the four types of genes typically mutated in cancer.
Four classes of normal regulatory genes – growth-promoting proto-oncogenes, growth-inhibiting tumor suppressor genes, genes that regulate programmed cell death (apoptosis), and genes involved in DNA repair.
Using only a few sentences for each, list the 8 essential alterations involved in malignant transformation of cells.
The fundamental changes in cell physiology that together determine malignant phenotype are:
- Self-sufficiency in growth signals (proliferate without external stimuli)
- Insensitivity to growth-inhibitory signals
- Evasion of apoptosis
- Limitless replicative potential (avoid senescence)
- Sustained angiogenesis (necessary for the tumor to grow)
- Ability to invade and metastasize (tumor metastases are the cause of the vast majority of cancer deaths and depend on processes that are intrinsic to the cell or are initiated by signals from the tissue environment)
- Defects in DNA repair (leads to genomic instability and mutations)
- Escape from immune attack
Proto-oncogene
The unmutated normal proto-oncogenes make the proteins involved in the above pathways (growth factors, growth factor receptors, signal transducing proteins, nonreceptor tyrosine kinases, nuclear transcription factors, cyclin and cyclin-dependent kinases, etc.).
Oncogene
Created from mutations in pro to-oncogenes.
oncoprotein
Resemble the normal products of proto-oncogenes except that the oncoproteins are often devoid of important regulatory elements, and their production in the transformed cells does not depend on growth factors or other external signals. This change promotes autonomous growth.
For a given proto-oncogene , how many alleles are typically mutated in order to generate an activating mutation?
Generally, only one allele needs to become mutant to create an effect.
List some of the functional types of proto-oncogene mutations.
ABL-BCR fusion gene: results in increased tyrosine kinase activity (treat with tyrosine kinase inhibitor imatinib mesylate).
HER 2/neu: results in over expression of cell membrane epidermal growth factor receptor (in breast cancer, treat with monoclonal antibody to Her2/neu receptor, trastuzumab (Herceptin).
RAS: results in persistent activation of the RAS signal (KRAS for colon cancer; presence of
KRAS in colon cancer can be predictive of lack of response to certain forms of chemotherapy).
BRAF: associated with melanomas.
KIT: results in activation of tyrosine kinase receptor c-KIT (occurs in gastrointestinal stromal tumors, treat with tyrosine kinase inhibitor imatinib mesylate).
Explain the rationale of performing Her2/neu testing in breast cancer and KRAS mutation analysis in colon cancer.
Approximately 25% of breast cancers overexpress an epidermal growth factor
called HER-2/NEU. Patients who are HER-2/NEU positive can be treated with a monoclonal antibody to the Her2/neu receptor, trastuzumab (Herceptin).
Rationale for the use of KRAS mutation analysis for advanced colon cancer. A, simplified schematic of the EGFR signaling cascade. B, EGFR monoclonal antibody blocks binding of the growth factor, preventing downstream signaling. C, Mutations in the downstream signaling cascade (such as mutated KRAS) leads to activation of the signaling pathway, regardless of the monoclonal antibody. KRAS mutations are found in 40% of CRC.
Explain the “two hit” hypothesis for suppressor gene defects.
In contrast to oncogenes, both alleles for tumor suppressor genes need to be damaged for loss of growth inhibition (i.e., homozygous for the mutant allele, or, if one mutant allele is inherited, when the cell loses heterozygosity for the normal gene (known as loss of heterozygosity), although there are exceptions). This is known as the “two hit” hypothesis, and it explains the sporadic and inherited occurrence of identical tumors.
State the malignancies associated with inheritance of BRCA1/2 and APC mutations.
BRCA1/2
-Breast, ovary, prostate carcinomas
APC
-Familial polyposis (colorectal carcinoma)
Describe how overexpression of BCL-2 can lead to follicular lymphoma.
Apoptosis can occur through two pathways, an extrinsic death receptor pathway and a mitochondrial pathway. Defects can occur at several key points (numbered). One example involves BCL2 gene products which regulate and prevent apoptosis by limiting the release of cytochrome c. 85% of B-cell lymphomas of the follicular type carry a characteristic t(14;18) translocation which results in overexpression of the BCL2 protein. This protects the lymphocytes from apoptosis, allowing them to survive for long periods. Because BCL2-overexpressing lymphomas arise in large part from reduced cell death rather than explosive cell proliferation, they tend to be indolent (slow growing) compared with many other lymphomas.
Describe how overexpression of telomerase can lead to limitless replication.
Most normal human cells have a capacity of 60-70 doublings, after which the cells lose their ability to divide and become senescent. This phenomenon is related to progressive shortening of the telomeres at the end of the chromosomes (telomeres prevent gene loss after multiple cell divisions, and short telomeres are recognized by the DNA-repair machinery as damaged DNA, leading to cell cycle arrest). Maintenance of telomeres is seen in virtually all types of malignant neoplasms, and in most cases, is due to the up-regulation of the enzyme telomerase (unlike malignant neoplasms, most benign neoplasms have normal telomerase activity).
Describe how cancer cells can initiate neoangiogenesis. What cytokine is typically involved?
Solid tumors cannot enlarge beyond 1 to 2 mm in diameter unless they are vascularized. Cancer cells can stimulate neoangiogenesis, during which new vessels sprout from previously existing capillaries, or vasculogenesis, in which endothelial cells are recruited from the bone marrow. The tumor vasculature is abnormal; the newly formed vessels are leaky, dilated, and have haphazard connections. Angiogenesis is required not only for continued tumor growth but also for access to the vasculature and hence metastases. It is thought that angiogenesis is controlled by an increase in the production of angiogenic factors (such as VEGF) and/or a loss of angiogenic inhibitors. The factors may be produced by the tumor cells, by inflammatory cells (e.g. macrophages), or by stromal cells associated with the tumors. Numerous mediators and pathways have been proposed, and antiangiogenesis therapeutic agents have been created (e.g. monoclonal antibody to VEGF (vascular endothelial growth factor) .
Using just a few sentences, describe the steps involved in invasion and metastases. List some of the ways that cancer cells can evade immunologic detection.
Invasion and metastasis are the biologic hallmarks of malignant tumors and are the major cause of cancer-related morbidity and mortality. Remarkably, millions of tumor cells may be released into the circulation each day, but only a few metastases are produced, and some patients will never get metastases. Production of metastases involves two major steps:
Invasion of the extracellular matrix (ECM): this involves dissociation of tumor cells from one another, degradation of the basement membrane and interstitial connective tissue (or alternatively, ameboid migration through the basement membrane), attachment of the tumor cells to ECM proteins, migration of tumor cells within the ECM, and intravasation into blood vessels.
Vascular dissemination, homing of tumor cells, and colonization: once in the blood, tumor cells may attach to the endothelial cells of the first capillary bed available to the tumor; however, it is well known that certain tumors have preferential spread to certain organs. Such organ tropism may be related to different expression of endothelial adhesion ligands in the capillary beds of various organs, as well as different chemokine receptor expression in the various tumors. Colonization results from tumor cells secreting cytokines, growth factors, and ECM molecules that make the metastatic site habitable for the cancer cell (e.g. breast cancer metastatic to bone can activate osteoclasts, producing osteolytic lesions)
