The Cell Cycl e

 New cells arise when one cell divides or t w o cells (like sperm and egg) fuse.

 These events initiate a cell-replication program that is encoded in the DNA and executed by prot eins.

 A period of cell growth, and replication of DNA is then followed by cell divisi on.

 Cell growth and divi sion is hi ghly regulat ed in the body.

 Cancer occurs when a cell escapes fro m this regulat ion and growth is unchecked .

Most eukaryotic cells live acco rding to an internal cl ock, they proceed through a series of phases called the cell cycle .

 G 1 : the g ap between the end of m itosis and beginning of S phase

 S phase : DNA is duplicated: cells have a DNA content that progressivel y increases from 2n to 4n.

 G 2 : tim e between the end of S and the beginning of m itosis

 M - m itosis: Cell division: t h e two daught er cells receive all of the genetic inform ation of the parent cell.

 G 0 : quiescent cells, not actively cycling.

G1 and G2 are periods of apparent inactiv ity between the maj o r discernable ev ents in the cell cycle.

 Bacteria can replicat e their single chrom o some and divide in about 20 m i nutes.

 Most m a mmalian cells have a cell cycle time on the order of 10-12 hours.

 Som e cells (nerve cells, striated m u scle cells) do not divide at all. They have tem porarily exited from the cell cy cle and ent e red a quiescent state called G 0 .

Checkpoints

“Proofreading before division”

Progress through the cell cy cl e is regulated at key check p oints along the way that m onitor the status of the cell.

Before entering m ito sis, the integr ity of the DNA is checked. Exposure t o radiation causes a block in G 2.

[Lodish, 2000]

Mitosis is the process for partitioning the genome equally duri n g cell division.

The mitotic apparatus captures the chrom o somes and pulls them to the opposite sides of the dividing cell.

 Prophase : the replicated chrom o somes (each containing two identical chrom a tids) are condensed and releas ed to the cytoplasm when the nuclear m e m b rane breaks down.

 Metaphase and anaphase: the chromosomes are so rted and moved to opposit e ends of the cell.

 Telophase : marks the end of mitosis as a mem b rane is reform ed around each set of chromoso mes.

 Cytok i nesis : division of the cytoplasm and separation of t h e two daughter cells.

What’s cancer?

Cancer -uncontrol l ed cell growth

 Tumor - mass formed by growing cancer cells

 Malignant - destructive, invasive, can met a stasize

 Benign - slowly growing, does not invade surroundi ng tissues or m e tastasize, usually encapsulated .

 Metastasis - spread of the tum o r cells to ot her sites, where they establish secondary areas of growth.

 Angiogenesis - both prim ary and secondary tum o rs require new blood vessels to sustain growth.

E.g. ,

 Carcinom a - solid tum o r arising from epithelia l tissue such as skin, colon, lung, breast.

 Sarcoma - solid tum o r arising from connective tissue such as bone.

T u m o r	T i s s u e
Malignant
Adenocarcin o m a	Glandular
Carcinom a	E p i t h e l i a l
Gliom a	Glial c e lls in CNS
Hepatom a	L i v e r
Leukem i a	W B C s l e u k o c y t e s
Lym phom a	l y m p h o c y t e s
Melanom a	P i g m e n t c e l l s
Myelom a	Plasm a cells (bone m a rrow)
Nephroblastom a	K i d n e y
Neuroblasto m a	N e r v e c e l l s
Retinoblastom a	E y e ( r e t i n a )
Sarcom a	C o n n e c t i v e t i s s u e
Se m i nom a	R e p r o d u c t i v e c e l l s
Squa m o u s	E p i d e r m a l
Usually ben i gn
Adenom a	G l a n d u l a r
Chondrom a	C a r t i l a g e
Fibrom a	F i b r o b l a s t s
Osteom a	B o n e
papillom a	S u r f a c e e p i t h e l i a

Cancer cel ls can mul tiply in t h e absence of norm a lly required growth factors and are resistant to signa ls that normally program cell d eath.

Malignant cells show m a ny differe nces from normal counterparts.

 Less well differentiated

 More rapid growth

 Loss of normal attachments to ne ighbors, loss of contact inhibition

 Growth factor independent cell growth

 Genetically unstable (phenot ype and genotype can change with time)

 Disruptions to cytoskeleton

 Higher m e tabolic rate

 Changes i n cytoplasmi c ion co ncentrations

G e ne s inv o l ve d in c a nc er

Seven types of proteins participat e in the control of cell growth.

Oncogenes - cancer causing genes

Many oncogenes are altered fo rm s of normal cellular ge nes called proto-oncogenes Gain-of-function m u tations convert proto-oncogenes into oncogenes.

Tumor su ppressor genes - genes which code for cell cycle control proteins

 Loss-of-function m u tations in t u m o r suppressor genes are oncogenic.

 Usually act recessively, both copies m u st be deleted or m u tated to lose the norm a l cell growth suppressi on effect.

Multi-step progression of cancer

Develop m ent of cancer re quires several mutations

Consistent with the o b servation of in creas ed incidence as a function of age

 Cancer: a clone from a single cell?

 Colorectal car cinoma well studied with biopsy m a terial and genetic analysis at all stages of developm ent.

o Visible on endoscopy

o Biopsy material avail a ble

o Analyze genetic m u tations

Carcin o gens - agents that can caus e cancer

Viruses - can introduce oncogenes, or suppre ss genes that inhi bit cell growth

 Retroviruses - RNA viruses, integrate into the genome of the i n fected cel l as a DNA copy and can carry oncogene s derived from cellular proto- oncogenes.

 DNA tumor viruses - contain oncogenes of purely viral origi n

Chemi c als - usually thought to act as carcinogens by causing DNA damage.

 Som e of the m o st potent are alkylating agents that are capabl e of adding organic groups to D NA.

 Others, (polycyclic hydrocarbons) b ecome carcinogenic when they are biochem i cally m odified in cells, ofte n as the cell attem p ts deto xification

 Phorbol esters- do not cause DNA damage, but prom ote growth (may only work when DNA damage also occurs from another agent)

Radiation - also thought to act by causing DNA danage

 UV - is absorbed directly by DNA, causi ng base ch anges, in s unlight can lead to skin cancer.

 Ioniz i ng radiation i s actually a relatively weak carcinogen.

Apoptosis - now recognized that cancer is due not only to uncontrol led cell growth, but also to loss of control i n regulated cell growth.

In an adult, normal ti ssues are i n homeost asis- no net increase i n cell nu mbers because of a bal a nce between cell divisi on and cell death due to apoptosis.

Apoptosi s vs. Necrosis