Þ as the tumor cells grow, they undergo new mutations Þ difficult to treat tumors due to this heterogeneity
Which factors differ amongst these different subclones?
growth factors
gain or loss of adhesion molec
antigenic properties
angiogenesis factors (produce more to stimulate growth)
cytokines
enzyme expression
Thus, a growing tumor tends to be enriched with those subclones that "beat the odds"
Tumor Progression
:
Over time, many tumors become more aggressive
Þ often incremental; multiple mutations (?genomic instability)
Result
Þ tumor heterogeneity
Experiment
: implanted tumor cells into tail vein of rats Þ lung metasteses
some grew more colonies than others (why?)
next, performed a limiting dilution experiment
flask A: 1 clone
Þ inject Þ all subjects had a few lung colonies
flask B: 1 clone
Þ inject Þ all subjects grew many lung colonies
conclusion: original injection was from a heterogenous colony
Metastasis
general features:
Tumor implants discontinous with primary tumor
Most cancers metastasize (but not all)
Tumors more likely to metastasize Þ more aggressive, more rapidly growing, larger
Probability of metastasis cannot be judged from examination of 1° tumor
At diagnosis:
30% of patients have clinical metastases Þ directly find the metastases
30-40% have occult metastases due to relapse Þ didn’t find the metastases (but infer one is present)
metastatic cascade:
Epithelial cells (sticky surface due to E cadherin) Þ tumor epithelial cells (ß E cadherin) Þ lose stickiness so able to leave home (detachment) Þ hit basement memb (BM) Þ have Ý expression of receptors for BM (laminin) and extracell matrix (collagen type IV) Þ attachment to BM Þ proteolytic enzymes (3 classes: see below) Þ dissolve BM (degradation) Þ bind collagen type IV Þ dissolve thru extracell matrix (migration); locomotion tumor-derived cytokine or autocrine motility factor Þ bind to endothelial cells of vasculature (attachment) Þ proteolytic enzymes (degradation) Þ intravasation between endothelial cells Þ form clusters with themselves and other host cells for protection in this turbulent environ Þ tumor cell emboli Þ adherence to BM of distant organ (attachment) Þ degradation and extravasation Þ migration into organ Þ angiogenesis for growth (if not, grow 1-2mm, then death) Þ growth of tumor cell (metastasis)
Host works to interrupt this process
Death of 75% of patients due to metastatic sites
molecular changes in metastasis
Adhesion molecule
: E-cadherin, CD44
Proteases
:
Serine-protease
: urokinase-type plasminogen activator
Cysteine-protease
: Cathepsin D, B, L
etalloprotease
: collagenase IV or inactivation of TIMPS (tissue inhibitors of metalloproteases)
Receptors
(integrins): for laminin, ECM
Cytokines
: host plus autocrine motility factor
Metastasis genes
: nm23 or TIMPS
host has gene (nm23) that inhibits metastases Þ if gene is missing Þ cells can metastasize
nm23 is not universal but may be a specific gene for breast cancer
TIMPS also found to inhibit metastases
pathways of spread
Direct seeding
(ie. ovarian cancer); never reaches lymphatics/vasculature
Lymphatic spread
: most common initially; enlarged regional lymph node
Hematogenous spread
: <0.01% malignant cells survive
Colon cancer metastases: liver and lung
Breast cancer metastases: lung (59%), liver (58%), bone (44%), Pleura (37%), adrenals (31%), skin (34%)
Lung cancer metastases: pleura (60%), adrenals (50%), liver (41%), bone (36%), CNS (37%), skin (0%)
patterns of spread
Observation
: each type of cancer metastasizes to specific organs