Cancer Biology

CANCER HALLMARKS & STEM CELLS

Alexander Drilon

Hallmarks of Cancer

CAs share a set of common distinctive & complementary capabilities that enable tumor growth & met dissemination (Cell 2011;5:646)

Figure 4-1

Cancer Stem Cells

Characterized by self-renewal & ability to differentiate; found in a variety of CAs including AML, CML, gliomas, breast CA (NEJM 2006;355:1253)
Two pathways involved in regulation of pattern formation during ontogeny
- Wnt pathway: (1) WNT ligands bind to FZD (Frizzled) receptor, (2) disrupts assembly of a complex (AXIN, APC, CK1, GSK3) that tags CTNBB1 (β-catenin) for degradation, (3) CTNBB1 moves to nucleus → binds TCF/LEF freeing it from TLE (Groucho), (4) CTNBB1 & TCF/LEF activate target genes (eg, CCND1, MYC); FAP develops 2° to germline inactivating Mt of APC (Nat Rev Cancer 2013;13:11)
  
  Figure 4-2
- Hedgehog pathway: (1) HH ligands SHH (Sonic), DHH (Desert), & IHH (Indian) bind to PTCH1 (Patched) releasing inhibitory effect on SMO (Smoothened), (2) causes dissociation of protein complex including SUFU, PKA, & GLI, (3) GLI translocates to nucleus to (4) activate target genes; BCCs w/activating SMO Mt or inactivating PTCH1 Mt, Gorlin syndrome (BCCs, medulloblastomas, rhabdomyosarcomas) w/germline PTCH1 Mt (Nat Rev Cancer 2008;8:743)
  
  Figure 4-3

MECHANISMS OF ONCOGENESIS

Alexander Drilon

Carcinogenesis often proceeds in a multistep fashion w/the acquisition of several genomic aberrations via Mt, amp, rearrangements, & infxn

Mutations

Alterations in DNA sequence or structure 2° to replication errors or carcinogens: Mt may be activating or inactivating

Type of Mutation	Examples
POINT Mt: Base substitution transition G:C ⇔ A:T transversion A:T ⇔ T:A, G:C ⇔ C:G Can be silent (no change in AA) nonsense (early stop codon) missense (change in AA)	*JAK2* V617F in polycythemia vera (PCV), ET *BRAF* V600E in melanoma, hairy cell leukemia (HCL) *KRAS* G12A in CRC, NSCLC *EGFR* L858R in NSCLC Note: 1st letter—original AA, number—AA position, 2nd letter—substituted AA, (EGFR L858R, ie, leucine at position 858 replaced w/arginine)^*
DELETION: Deletion of one or more bases or larger stretches of material w/in chromosomes	*EGFR* exon 19 del in NSCLC 5q- syndrome in MDS
INSERTION: Insertion of one or more bases	*ERBB2 (HER2)* exon 20 ins in NSCLC
^*Amino Acid Nomenclature: Arg (R), His (H), Lys (K), Asp (D), Glu (E), Ser (S), Thr (T), Asn (N), Gln (Q), Cys (C), Sec (U), Gly (G), Pro (P), Ala (A), Val (V), Ile (I), Leu (L), Met (M), Phe (F), Tyr (Y), Trp (W)

DNA Amplification

Selective ↑ in the number of copies of a gene (copy number alteration), mechanism by w/c the expression of a gene is enhanced above physiologic levels
Clinically relevant egs:
- ERBB2 (HER2) Amp: BC (average of >6 gene copies/nucleus or HER2/CEP17 ratio >2.2 via FISH), gastric CA, predictive of response to HER2-targeted therapies (Nat Rev Clin Oncol 2011;9:16)
- FGFR1 Amp: In squamous cell NSCLCs (Sci Transl Med 2010;2:62ra93)

Chromosomal Rearrangements

Result in creation of a gene fusion w/potent oncogenic activities: Novel sequences are juxtaposed to coding sequence of a TK domain or transcription factor → constitutive activation of TK or downstream target genes of transcription factor

Type

Examples

Translocation: Rearrangement of material between nonhomologous chromosomes

Reciprocal—even exchange of material

Robertsonian—2 acrocentric chromosomes fuse near centromere w/short arm loss

BCR-ABL1 t(9;22) in CML/Ph+ALL

PML-RARA t(15;17) in APL

NPM1-ALK t(2;5) in ALCL

RUNX1-RUNX1T1 t(8;21) in AML M2

EWSR1-FLI1 t(11;22) in Ewing sarcoma

Inversion: Chromosomal segment is reversed end-to-end (pericentric—includes centromere vs. paracentric—doesn’t include centromere)

EML4-ALK t(2;2) in NSCLC

CBFB-MYH11 inv(16) in AML M4 w/eosinophilia

Deletion: Genetic material lost w/in a chromosome (interstitial)

TMPRSS2-ERG del(21) in prost CA

FIP1L1-PDGFRA in hypereosinophilic syndrome

Infections

Play important roles as carcinogens in several diseases (see Cancer Epidemiology Chap. for more extensive list), carcinogenesis occurs through a variety of mechanisms eg, via the actions of viral/bacterial proteins, insertional mutagenesis
- Viruses: HPV (cervical CA, oropharyngeal squamous cell CAs of the head & neck, viral proteins E6 & E7 inhibit TP53 & Rb1, respectively), EBV, KSHV
- Bacteria: H. pylori (gastric CA), bacterial CagA protein → activates tyrosine phosphatase SHP2 affecting various pathways involved in cell migration, adhesion, & apoptosis

GROWTH FACTOR SIGNALING

Alexander Drilon

Oncogenes vs. Tumor Suppressor Genes (TSGs)

Oncogenes: Contribute to the development or maintenance of the neoplastic phenotype, converted from protooncogenes w/c have nl functions that are involved in cell differentiation, proliferation, & apoptosis → these may sustain gainof-function or activating Mt that result in constitutive activation (NEJM 2008;358:502)
- Oncogene addiction: Process by w/c tumor cells become highly dependent on an oncogenic protein or pathway for sustained proliferation or survival, 1° driver Mt in oncogenes are often mutually exclusive (Cancer Res 2008;68:3077)
- Many oncogenes encode growth factor receptors or proteins involved in cell signaling
TSGs: Encode proteins responsible for inhibiting tumor formation or maintenance, involved in processes like DNA repair & apoptosis

Growth Factor Signaling

Initiated by ligand binding to growth factor receptors that activate downstream pathways; mechanism by w/c an extracellular signal is transduced through a cell, resulting in a change in gene expression, modifying specific cellular processes

Figure 4-4 Growth factor signaling: Ligand binding (eg, EGF, TGFα, epiregulin) → receptor dimerization & phosphorylation of intracellular TK domains → downstream pathway activation; ↑ pathway activity mediated by signal transduction proteins (protooncogenes) of MAPK and PI3K pathways, negative regulators (TSGs) shown in white → ultimately affect processes such as cell survival & proliferation, differentiation, angiogenesis, etc.

Can be targeted by mAbs (eg, bevacizumab for VEGF, cetuximab for EGFR, see Monoclonal Antibodies Chap.) or small molecules (eg, TKIs)

Growth Factor Receptor	Role in Carcinogenesis/Examples
ERBB family: Structurally related receptors, capable of forming homo or heterodimers, contain TK domains (except for ERBB3 or HER3) (Nat Rev Cancer 2005;5:341)
EGFR (ERBB1) ERBB2 (HER2) ERBB3 (HER3) & ERBB4 (HER4)	EGFR Mt in lung CA, EGFR overexpressed in lung adenoCA, glioblastoma, HNSCC ERBB2 (HER2) Amp & ERBB2 (HER2) overexpression: breast CA & gastric CA Dimerize w/other family members, overexpressed in a number of malignancies
FGFRs: FGFR1, FGFR2, FGFR3, FGFR4 (Nat Rev Drug Discov 2009;8:235)	FGFR1 Mt in glioblastomas & Amp in squamous NSCLC FGFR3 Mt & FGFR3 overexpression in bladder CA
MET (HGFR)	MET Mt in sporadic/hereditary papillary RCCs
KIT	KIT Mt in GIST, melanoma, mast cell leukemia
PDGFRA	PDGFRA Mt in GIST, role in angiogenesis
VEGFR	Angiogenesis, overexpressed in a variety of CAs
IGF1R	Insulin signaling, potential predisposition to several CAs