Table 6.
Priority targets for sustained proliferative signaling
| Targets for sustained proliferationa | (inhibits) HIF-1 signaling | (inhibits) NF-κB signaling | (inhibits) PI3K/Akt signaling | (inhibits) Wnt (β-catenin) | (inhibits) IGFR1 signaling | (attenuates) cell cycle (CDKs/cyclins) | (suppresses] AR signaling | (suppresses) ER signaling |
|---|---|---|---|---|---|---|---|---|
| Other cancer hallmarks | ||||||||
| Genomic instability | + [484,635]b |
+ [485] |
+ [486] |
0 | 0 | + [487] |
+ [488] |
+ [489] |
|
Tumor-promoting inflammation |
+ [490] |
+ [491,492] |
+ [493-495] |
+ [496-498] |
+ [499,500] |
+ [501,502] |
+/− [503,504] |
+/− [505.506] |
|
Evasion of anti- growth signaling |
0 | +/− [507] |
+ [508,509] |
+ [510.511] |
+ [512,513] |
+ [514,515] |
+ [516-518] |
+ [519,520] |
|
Resistance to apoptosis |
+ [521,522] |
+ [523,524] |
+ [525] |
+ [526] |
+ [527] |
+ [528] |
+ [529] |
+ [530] |
|
Replicative immortality |
+ [531] |
+/− [225,532,533] |
+ [534-536] |
+/− [537.538] |
+ [706,707] |
+ [539.540] |
+ [541,542] |
+ [543-546] |
|
Deregulated metabolism |
+ [45,547,548] |
+ [549] |
+ [548,560] |
+ [561] |
+ [562.563] |
+ [564,565] |
0 | + [566] |
|
Immune system evasion |
0 | + [567] |
+ [568] |
+ [569,570] |
0 | − [571,572] |
+ [573,574] |
+ [575,576] |
| Angiogenesis | + [727] |
+/− [355,577] |
+ [578,728,646] |
+/− [579,636] |
+ [580] |
+ [582] |
+ [583] |
+/− [584,585] |
|
Tissue invasion and metastasis |
+ [5,585] |
+ [586,587,708] |
+ [588] |
+/− [589] |
+ [563,590] |
− [591,592] |
+/− [593] |
− [594] |
| Other characteristics | + [595] |
+ [596] |
+ [597] |
+ [598,599] |
+ [600] |
+ [601,602] |
+ [603] |
+/− [601,604-606] |
|
Tissue interactions in the tumor microenvironment |
The cross validation above documents whether the therapeutic targets that are important to block sustained proliferative signaling also block additional hallmarks of cancer as indicated by the cited references. In identifying these putative therapeutic targets, + = putative target in sustained proliferative signaling that is shared with other hallmarks (complementary relationship); 0 = putative target not documented in other hallmarks (no relationship); +/− = putative target whose inhibition would promote other selected hallmarks (making it controversial as to whether the molecule/pathway should be targeted in cancer at all); − = putative target that promotes sustained proliferative signaling but inhibits other selected hallmarks (target inhibition has opposite effects, depending upon the hallmark; suggesting a contrary relationship). For example, HIF-1 is activated by mutation, confers resistance to apoptosis, supports replicative immortality, deregulates cell metabolism, stimulates angiogenesis, metastasis, and alters tumor microenvironment. All of these features promote tumorigenesis, suggesting it is a good target for therapeutic intervention in multiple steps of tumor pathogenesis.
The numbers in each box are the references that document whether the putative therapeutic target in each column is also a target for the other hallmarks.