12_Cancer Cells

Cancer (CA)

• is a cellular malfunction that has progressive consequences deterrent to normal cells. CA cells are mutant cells that have gone wild as they are.

• 2nd leading cause of death, abnormalities in cell function

• Cellular defects: underlying gene mutation & altered gene expression

• The resulting mass of growing tissue is called a tumor (or neoplasm). Although, commonly tumors have escaped from the normal controls on cell proliferation, tumor cells do not always divide more rapidly than normal cells.

• Crucial in Cancer Development: Tumors arise due to disrupted balance: Cell division : Cell differentiation or Cellular death. (Not the Rate of cell division!)

tumor

• The resulting mass of growing tissue is called a ___ (or neoplasm).

• Although, commonly ____have escaped from the normal controls on cell proliferation, tumor cells do not always divide more rapidly than normal cells.

a. Molecular and genetic defects (copy of the mutated gene - oncogene)

b. Occasion malfunctions within the cells or group of cells

c. Originate in almost any organ; depending on the cell type involved

CA can develop with any of these causes:

1. Ability of the cells to proliferate in defiance of the normal constraints

2. Ability to invade and colonize territories normally reserved for other cells.

Oncogenes are genes that when activated, Cancer Cells can evade the normal checkpoints in cell cycle. CA cells have Heritable properties, that is dependent on 2 properties:

1. They have reduced dependence on signals from other cells for their growth, survival and division.

2. They are less prone to kill themselves by apoptosis than normal cells.

3. They can often proliferate indefinitely.

4. They are genetically unstable, with greatly increased mutation rate.

5. They are abnormally invasive (lack specific cell-adhesion molecules, such as cadherins).

6. They often survive and proliferate (hyperplasia) in foreign tissues to form metastases, whereas most normal cells die when misplaced

7. These cells can exhibit "pleiomorphism" (Pleiomorphic cells – cell shape are unusual from normal cells).

CA cells have adaptation and one of their key adaptation and feature is that:

Tyrosine kinase-dependent receptors

are connected to growth factors, take for instance, the role of insulin interaction in insulin receptors that can be mediated by IGFs or insulin-like growth factors.

Tyr kinases

can lead generation of secondary messengers such as PIP that is important for movement and release of intracellular Ca2+ ions.

Tyr kinases

can lead generation of secondary messengers such as PIP that is important for movement and release of intracellular Ca2+ ions.

Pleiomorphic cells

cell shape are unusual from normal cells

angiogenesis

CA cells exhibit different shapes and forms (pleiomorphism) and builds its own blood supply network by inducing ___

integrin.

Anchorage by binding to the extracellular matrix through cell surface proteins called

Apoptosis

• involves nuclear changes and DNA fragmentation, cytoplasmic lysis, then transforms into apoptotic bodies or cell shrinkage.

• can be triggered by both internal and external factors

• early death of cell; preprogrammed activity – nuclear changes, cytoplasmic lysis (apoptotic caspases activity), then transforms into apoptotic bodies.

apoptotic bodies or cell shrinkage

Apoptosis involves nuclear changes and DNA fragmentation, cytoplasmic lysis, then transforms into

misfolded proteins and deregulated signalling

Apoptosis can be triggered by both internal and external factors. Internal factors include ___

nutrient loss, radiation, heat and activation of cell surface receptors, such as TNF and FAS

Apoptosis can be triggered by both internal and external factors, external factors include ___

“CASPASES”

Apoptotic enzymes or ___becomes activated and performs proteolysis (cleavage of proteins or protein degradation) and lead to another caspase proteolysis event to invoke proteolytic cascade event.

Cytochrome c

serves as a precursor for caspase enzyme, wherein one of the key organelles in apoptosis is the mitochondria

proteolysis

Apoptotic enzymes or “CASPASES” becomes activated and performs ___ (cleavage of proteins or protein degradation) and lead to another caspase ____event to invoke proteolytic cascade event.

Fas ligand (FasL)

• is a type II membrane protein that belongs to the TNF superfamily.

• It is found in organs such as eye, testes and brains and can induce apoptotic cell death in cells that express Fas.

• is part of the TNF receptor family and is found on lymphocytes or immune cells.

• It is believed that apoptosis is one method of immune privilege in these organs.

• It should be added that others may not feel it is the only way that cell death can occur among invading auto-aggressive cells, but there is enough provocative evidence to suggest that it at least should be considered.

intervening telomere production and telomerase activity

One of the targets in CA chemotherapy is _____, but diagnostic biomarkers for precise target of telomeric length is still lacking in CA research.

NEOPLASIA

Another term for cancer cell proliferation or CA disease is called

Basement membranes (BM)

• provide the cellular boundary, nourishing normal cells through diffusion of nutrients through intercellular junctions like tight, adhering, and gap junctions.

• serve as an effective layer in between tissues, so that basic tissues comprising the organ will carry out their distinct cellular functions.

1.TUMOR CELLS must be able to detach themselves from other normal cells. This involves processes to lyse the cell to cell adhesion molecules (cadherin,selectin).

2.TUMOR CELLS must move and attach themselves to the basal membrane (basement membranes), and lyse the membrane.

3.TUMOR CELLS must migrate into the stroma and must overcome the tissue defenses by producing enzymatic complexes à collagenase typeV, metallo-proteinases, etc.

Cellular invasion by tumor cells can be potentially invade stroma due to the ff. features of TUMOR CELLS:

1) cellular detachment (independent-anchorage), thereby evading the "housekeeping" of phagocytic cells, followed by

2) attachment of tumor cells to new microhabitat.
3) lysis where proteolytic enzymes and activation of kinases can promote signals for tumorigenic formation.

4) migration of cells involving displacement of normal cells and occupation of CA cells in the normal microhabitat

5) angiogenesis formation of new blood vessels

6) adhesion to create an independent-anchorage of tumor environment distinct from other cells, usually CA cells protect themselves with enriched vascularization.

7) metastasis

(DALMAAM)

Once TUMOR CELLS occupied the stroma, it is now possible for them to spread across and invade other tissue microhabitats. The stage of metastasis involves:

VEGF (vascular endothelial growth factor)

• promoter of angiogenesis

• signals hemangioblasts, as precursors of vascular endothelial cells to undergo vasculogenesis

Vasculogenesis

involves proliferation of endothelial cells, mural cells, pericytes and smooth myofibers (SMC).

Hematopoietic stem cells

contribute to angiogenesis by differentiating to leukocytes or platelets, both of which release angiogenic factors.

AVASCULAR phase

Small, benign tumors is under 1st phase,____ , with a controlled size of 1-2 mm in diameter. Their dormant (benign) activity rests on steady state between cell proliferation and apoptosis.

VASCULAR (angiogenic) phase

Benign types can grow exponentially and can become LARGE tumors, proceeding to the 2nd phase, ___

onset of angiogenic or angiogenic switch

The ___is discrete step that can occur at any stage of tumor progression, type of tumor and microhabitat.

potential tumorigenic spaces

Breast CA (BRCA) usually behave as malignant tumors due to the nature of the tissue enriched with stroma. CA cells can easily use them to proliferate as stroma are ___

Normal Cells

• For order and maintenance of the normal tissues, the individual cell must adjust its behavior according to the needs of the organism as a whole

• The cell must divide when new cells of its specific type are needed; it refrains from dividing when it is not needed

• The cell must live as long as it is required to live; and kill itself when it is required to die.

• It must maintain the appropriate specialized character;

• It must occupy its proper place; and not stray into inappropriate territories

Hippocrates, 5thcentury BC

Cancer was coined by

Crab

Cancer means __ in latin

disrupted balance: Cell division : Cell differentiation or Cellular death

Tumors arise due to

1. Deletion / Point Mutation

2. Gene Amplification

3. Chromosome Rearrangement

When does cancer occur?

Oncogenes

Causes cells to divide too rapidly

Tumor suppressor gene mutation

Mutation removes normal suppression of cell division

DNA repair gene mutation

Faulty DNA repair gene allows mutations to accumulate.

Anchorage-independent

Mechanisms of cancer cell proliferation:

• Normal cells do not grow well in culture if they are suspended in a liquid medium/semisolid agar but when provided with solid surface, the cells:

  • > can become anchored

  • > attach to the surface; spread out and begin to proliferate

Abnormalities in Apoptosis (CELL DEATH)

Mechanisms of cancer cell proliferation:

• The rate at which cells die influences growth of cancer cells

• cancer cells have various ways of blocking the pathways that trigger apoptosis

• preventing apoptosis allows cancer cells to survive and proliferate under conditions that would normally cause cell death

Mitochondria

achieves a special function in Apoptosis by releasing cytochrome c as a procaspase agent.

procaspase agent

The Mitochondria achieves a special function in Apoptosis by releasing cytochrome c as a ___

“EXCISION”

The most important repair is by ____

Cyclin

Cyclin-dependent kinases produces ___

retinoblastoma protein (pRb)

is a crucial tumor suppressor that regulates the cell cycle, prevents uncontrolled cell division, and helps maintain genomic stability.

Gap 1 (G1) phase

• cell grows in size, checks the status of its internal systems such as correcting any damage to the DNA

• the cell moves on through the cycle. If something is wrong and cannot be corrected, the cell ceases progression through the cycle and may initiate apoptosis and close down.

R

marks the point where restriction of the cycle can occur

synthetic (S) phase

the cell replicates its store of DNA in the chromosomes

p53

• is a tumor suppressor protein that binds to specific DNA sequences

• It is thought of as the "guardian of the genome" and controls the cell cycle to enable the repair of damaged DNA

"guardian of the genome"

p53 is a tumor suppressor protein that binds to specific DNA sequences. It is thought of as the _____ and controls the cell cycle to enable the repair of damaged DNA

VEGF

s a central mediator of ‘angiogenesis’, the formation of new blood vessels

Angiogenic switch

Results in overexpression of pro-angiogenic signals, such as VEGF

Benign

grows in a confined local area and is rarely dangerous

Malignant

is capable of invading surrounding tissues, entering the bloodstream and spreading to distant parts of the body. (“Cancer” refers to any malignant tumor)

Carcinomas

account 90% of all cancers, arise from the epithelial cells that cover external and internal body surfaces

lung, breast, colon

Cells of the ___Sarcomas are the most commonly affected by cancer

Sarcomas

develop from the cells of supporting tissues such as bone, cartilage, fat, connective tissue and muscles

Lymphomas

cancer of lymphatic origin in which the cancer cells grow as solid masses of tissue

Burkitt's lymphoma

is a rare, aggressive B-cell non-Hodgkin lymphoma, fastest-growing human tumor, often affecting children/young adults, characterized by a c-MYC gene translocation, and classified into endemic (Africa, tied to EBV/malaria), sporadic (worldwide), and immunodeficiency-related (HIV-linked) types

Leukemias

cancers that arise from cells of blood. The cancer cells reside and proliferate mainly in the blood stream (rather than growing as solid masses)