Description
This detailed oncology presentation outlines the fundamental biological capabilities, known as hallmarks, that cancer cells acquire to enable malignant growth and progression. The material explains the original six hallmarks—sustained proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis—alongside two emerging hallmarks: evading immune destruction and deregulating cellular energetics. Each hallmark is explored through specific mechanisms, such as mutations in signaling pathways (e.g., RAS-RAF-MAPK), loss of tumor suppressor functions (e.g., p53, RB), telomerase activation, and metabolic reprogramming like the Warburg effect. The resource is essential for medical students, oncology trainees, and practitioners in Zambia, providing a structured, molecular-level understanding of cancer biology crucial for exam preparation and clinical insights in a tertiary medical education context. Download these comprehensive notes to deepen your grasp of the core principles driving carcinogenesis.
What's inside
HALLMARKS OF CANCER HAMUYUNI CHISAMBA – BSc.HB, MBChB in progress What are the hallmarks of cancer? Biologic capabilities acquired by cancer cells during the multistep process of development of human tumors. Essential Alterations In Cell Physiology That Collectively Lead To Malignant Growth Of A Normal Cells. Originally six hallmarks of cancer proposed Self-sufficiency in growth signals Insensitivity to growth-inhibitory (antigrowth) signals. Evading apoptosis. Limitless replicative potential. Sustained angiogenesis. Tissue invasion and metastasis Two additional hallmarks of cancer are: Evading immune destruction. • Deregulating cellular metabolism or energetics 1.Sustained Proliferative Signalling Cancer cells : ‘master of their own destinies’ • Normal cells require growth signals to enter from a quiescent state into an active proliferative state. • These signals are transmitted into the cell through transmembrane receptors that binds to a particular class of signaling molecules. • Tumor cells generate their own growth signals and thereby reducing their dependence on external stimulation from their normal tissue microenvironment. Sustained Proliferative Signaling • Many cancer cells acquire the ability to synthesize abundance of GFs to which they are responsive, creating a positive feedback signaling loop Alteration of extracellular growth signals • Receptor overexpression may enable the cancer cell to become hyperresponsive to ambient levels of GF that normally would not trigger proliferation Alternation of transcellular receptor of those signals • Alterations in components of the downstream cytoplasmic circuitry that receives and processes the signals emitted by GF receptors can release a flux of signals into cells, without ongoing stimulation by their normal upstream regulators Alternation of intracellular circuits that translate those signals into action. Somatic Mutations activate additional downstream pathways that promote sustained growth • RAS-RAF-MAPK PATHWAY 90% Pancreatic adenocarcinomas carry mutant K-RAS alleles 40% melanomas contain activating mutations affecting B-RAF Sustained Proliferative Signaling Disruptions of Negative-Feedback Mechanisms that Attenuate Proliferative Signaling – • Defect in negative feed back mechanism leads to uncontrolled proliferative signaling . The prototype of this type of regulation involves the RAS oncoprotein. • The oncogenic mutations of RAS genes impair the intrinsic GTPase activity of RAS that normally serves to turn its activity off, ensuring that active signal transmission is transient. 2. Evading Growth Suppressors Growth suppressors are acting as the break mechanism to overrule the initiation or “turning off” of cell division. • The two prototype tumor suppressor genes encode the retinoblastoma (RB)-associated and P53 proteins. • The RB protein integrates signals from diverse extracellular and intracellular sources and, in response, decides whether or not a cell should proceed through its growth and division cycle. Role of TGF-B In normal cells, its exposure blocks their progression through the G1 phase of cell cycle; in many late stage tumors, however, its signalling is redirected away from suppression to activation of a cellular program termed “epithelial to mesenchymal transition” 3. Resisting Cell Death • Normally when cells become old or damaged they are programmed to die in a process called apoptosis. • But cancer cells escapes normal cell death and continue to accumulate in the body. • Tumor cells develops a variety of strategies to escape apoptosis. Anti apoptotic regulators • Most common is the loss of P53 tumor suppressor function, which eliminates this critical damage sensor from the apoptosis-inducing circuit. • Alternatively, tumors may escape apoptosis by increasing the expression of antiapoptotic regulators (Bcl-2, Bcl-XL Mcl- 1). • By downregulating proapoptotic Bcl-2–related factors (Bax, Bim, Apaf-1 ). Mechanisms of Contact Inhibition and Its Evasion Healthy cell stops dividing when comes in contact with other cells but cancer cell does not. • Merlin, the cytoplasmic NF2 gene product, activate contact inhibition by coupling cell-surface adhesion molecules like E- cadherin to transmembrane receptor tyrosine kinases. • Merlin strengthens the adhesiveness of cadherin-mediated cell-to-cell attachments and thus inhibits the mitogenic signals. • Thus, the mutation of NF-2 gene results in loss of this property and thus grow in uncontrolled manner. Autophagy Mediates Both Tumor Cell Survival and Death Nutrient starvation, radiotherapy, and certain cytotoxic drugs can induce elevated levels of autophagy that apparently protect cancer cells via resistance to apoptosis. • Moreover, severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy. • This particular survival response may enable the cancer cells to survive …
An extract of the text. Open the file below to read the full document.