The discovery of the first dependence receptor (DR) in 1998 [1] challenged the general dogma on transmembrane receptors, active only in the presence of their ligand. Indeed, our team unveiled receptors functioning in an either/or context rather than as conventional on/off switches. In effect, ligand-bound receptors activate a so-called “positive” signaling (proliferation, survival, differentiation), while unbound receptors transmit a “negative” pro-apoptotic signal (Figure 1). Hence, cells expressing DRs on their surface are dependent on the ligand for their survival, and these receptors have accordingly been termed “dependence receptors”. Currently, the DR family comprises around 20 members, homologous in their dual functionality. These known receptors may have one or several known ligands, and inversely a ligand may bind one or several receptors (Table 1).
Table 1: Table of the known Dependence Receptors and their respective ligands.
Dependence Receptor
|
Ligand(s) |
Reference |
Deleted in colorectal cancer (DCC) |
Netrin-1 |
[1] |
Uncoordinated homologs (UNC5H1, 2, 3, 4 or UNC5A, B, C, D) |
Netrin-1 |
[2,3] |
Neogenin receptor |
Netrin-1 Repulsive guidance molecule (RGM) |
[4] |
Neutrophin receptor p75 (p75NTR) |
Nerve growth factor (NGF) |
[5] |
Patched-1 (PTCH-1) |
Sonic hedgehog (SHH) |
[6] |
Cell-adhesion molecule-related/Down-regulated by Oncogenes (CDON) |
Sonic hedgehog (SHH) |
[7] |
Plexin-D1 |
Semaphorin-3E (Sema3E) |
[8] |
Rearranged during transfection (RET) |
Glial cell line-derived neurotrophic factor (GDNF) |
[9] |
Tropomyosin receptor kinase (Trk) A |
NGF |
[10,11] |
TrkB |
brain-derived neurotrophic factor (BDNF) |
[10,11] |
TrkC |
Neutrophine-3 (NT-3) |
[10,11] |
Ephrin type A receptor 4 |
Ephrin-B3 (EphB3) |
[12] |
MET or hepatocyte growth factor receptor (HGFR) |
HGF |
[13] |
Insulin receptor (IR) and insulin growth factor 1 receptor (IGF-1R) |
Insulin and insulin growth factor 1 (IGF1) |
[14] |
Anaplastic lymphoma kinase (ALK) |
Jelly belly (Jeb) |
[15] |
Integrins α and β |
2-{ethyl[(5-{[6-methyl-3-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]amino}isothiazol-3-yl)methyl]amino}-2-methylpropan-1-ol (EML) |
[16] |
Kremen-1 |
Dickkopf 1 (DKK1) |
[17] |
Notch3 |
Jagged 1 (Jag-1) |
[18] |
Latrophilin |
Contactin 6 (CNTN-6) |
[19] |
All of the receptors described above, when engaged by their specific ligands, transduce different pathways leading to the induction of cell differentiation, migration, inter-cellular communication or cell survival. These “positive” signaling functions are generally well-described, several of which are briefly presented below (Table 2). However in the absence of ligand binding these DRs triggers caspase-dependent cell death through pro-apoptotic mechanisms that have been reviewed previously [20] (Figure 2).
Table 2: Table of the known signaling triggered by DRs
Receptor/ligand pair |
Positive signaling induced
|
Reference
|
DCC or UNC5H/Netrin-1 |
PI3K and MAPK signaling pathway with a key role in axonal growth and orientation |
[21] [22] |
IR and IGF-1R/insulin and IGF-1 |
activate many pathways such as PI3K/Akt or Ras/MAPK required for glucose uptake, glycogen synthesis or proliferation |
[23] |
PlexinD1/Sema3E |
Ras activation, critical for hippocampus formation during the embryonic stage |
[24] |
Notch3/Jagged1 |
Activation of notch3 on vascular smooth muscle cells (VSMC) is essential for VSMC maintenance and maturation via activation of a canonical pathway including Notch3 intracellular cleavage (NICD) and NICD-dependent transcription |
[25] |
Aside from their common dual functionality, DRs are all highly involved in embryonic development and tumorigenesis. Their expression in the latter case is generally a factor of good prognosis, and it is generally admitted that tumors have developed escape mechanisms to evade this pro-apoptotic signaling either via a decrease in DR expression or an increase in ligand availability. Indeed, DRs limit tumor progression by eliminating supernumerary cells in a limited ligand environment, and thus constitute a natural mechanism to control cell growth [26]. As a consequence, tumor cells capable of counteracting it will have acquired a selective advantage. Two major mechanisms have so far been identified to bypass this control of cell death, namely the (i) silencing of the DR or its pro-apoptotic signaling pathway, and (ii) the autocrine production of the ligand (Figure 3).
This review will detail how tumors are able to develop by impacting either DRs or their ligands, and how such an interaction has become a target for personalized cancer therapies.
How to suppress a natural tumor suppressor
The prototypical DR, deleted in colorectal carcinoma (DCC), was originally identified in 1990 [27], and its gene located on chromosome 18q, a region prone to loss of heterozygosity (LOH), is frequently absent in colorectal cancers and more generally in a large fraction of cancers, resulting in the reduction or in the loss of DCC expression [27]. This LOH is mainly found in advanced stages of the disease, and its frequency increases with tumor progression [28-31], suggesting a role for DCC in cancer progression rather than initiation. Experiments seeking to restore DCC expression in tumor or metastatic lines demonstrated a reduction in ganglion invasion and prevention of metastatic spread of these cells to the lungs [32-35], arguing in favor of its role as a tumor suppressor in the late phases of tumor progression. The loss of DCC expression has been demonstrated in a variety of cancers [3,36,37], and results not only from a LOH but also through the hypermethylation of its promoter [3,38,39]. Although its rate of somatic mutation is relatively low in colon cancers (10-15%) [21], DCC is frequently mutated in sun-induced melanomas [40] and a single nucleotide polymorphism (SNP) in DCC has been identified in gallbladder cancer [37]. The role of DCC in cancer progression was first challenged in 1996 [21], prior to being associated with its DR function by our team in 1998 [1]. Mechanistically, we generated mice bearing a mutated DCC receptor with a non-functional pro-apoptotic activity. The absence of DCC-induced apoptosis was associated with the development of spontaneous intestinal tumors at low frequency and with increased adenocarcinoma when the DCC mutant mice were backcrossed with mice highly susceptible to spontaneous intestinal adenoma formation (APC mutant background) [41]. These DCC “death-dead” mutants displayed a tendency to develop both more colorectal cancers and lymphomas [42]. In another genetically-modified mouse model of mammary carcinoma based on the somatic inactivation of p53, the invalidation of DCC led to the appearance of metastases [43]. Hence, DCC, via its pro-apoptotic activity, is a strong tumor suppressor, and its mutation or suppression are highly advantageous for tumor cells.
Following the discovery of the role of this unique dual functioning DR in cancer progression, our team and others embarked in a research crusade to unveil other DRs potentially implicated in tumorigenesis. Uncoordinated homolog (UNC5H) receptors, in particular UNC5A, B and C, are often lost or greatly reduced in cancers [44,45]. The loss of expression of UNC5H in human primary tumors, as well as in cell lines, is mainly due to epigenetic mechanisms, such as the methylation of promoters [38,39,44,46]. Along this line, the promoter region of UNC5C is hypermethylated in nearly 80% of the colorectal tumors analyzed and its inactivation is associated with tumor aggressiveness [46]. In addition, invalidation of UNC5C is associated with intestinal tumor progression in mice [46]. Inversely, expression of UNC5A in various cancer cell lines, including colon cancer, reduces their ability to form colonies and induces apoptosis [47]. Moreover, UNC5A, B and D are p53 target genes, which participate in the pro-apoptotic activity of p53 [47,48,49].
Tropomyosin receptor kinase A was first identified as an oncogenic fusion protein [50–52], and this rearrangement is also found for TrkC in particular in congenital fibrosarcoma and acute myeloid leukemia [53,54]. Owing to their kinase activity, these receptors have been shown to play an important role in the biology of cancers, notably of neuronal or neuroendocrine origin. Surprisingly, despite their strong homology TrkA, B and C receptors behaved in a very dissimilar way. While TrkB is expressed in very aggressive tumors, the expression of TrkA and TrkC is associated with a good prognosis, at least in neuroblastoma and medulloblastoma [55,56]. These paradoxical findings are highly consistent with their dual functionality as DRs. Accordingly, as observed for netrin-1 receptors, TrkC is under-expressed in a large fraction of colorectal cancers in humans. This decreased expression is mainly due to promoter methylation [57]. However, to date, a functional demonstration that loss of TrkC or TrkA promotes tumor progression remains to be demonstrated mechanistically.
The Patched-1 receptor (PTCH-1), of the Sonic Hedgehog (SHH) morphogen, is a well-known tumor suppressor [58]. Loss of PTCH-1 expression, or mutations leading to its inactivation, has been observed in basal cell carcinomas and medulloblastomas [59]. It is generally accepted that the tumor suppressor activity of PTCH-1 is related to its repression of a canonical oncogenic pathway (Smoothened-Gli). However it was more recently shown to reduce the tumorigenicity via its DR activity [6]. However, there is currently no evidence in vivo that PTCH-1 functions as a tumor suppressor by its pro-apoptotic activity. This has nonetheless been demonstrated for another SHH receptor, namely the CDON receiver. High throughput sequencing has shown many false-sense mutations of CDON in human cancers (Sanger Institute Catalog for Somatic Mutations in Cancer web site, http://www.sanger.ac.uk/cosmic). In addition, loss of CDON expression has been observed in humans in tumors of the colon, kidney, lungs and breast [7]. Interestingly, the expression of CDON is inversely correlated with the tumor grade (according to the TNM classification) in colorectal cancers and mice mutated for CDON are prone to develop intestinal adenocarcinoma when backcrossed with APC mutant mice [7].
Among the other DRs, Kremen1, one of the latest to have been discovered, is down regulated in several cancers [17,60]. Mutations of Kremen1 in the domain responsible for the apoptotic activity induced by the receptor in the absence of its ligand DKK-1 were identified in cancer patients, supporting the view that these mutations confer a selective advantage for tumor cell survival [17]. Neurotrophin receptor p75 (p75NTR) is partially lost in the localized prostate tumor epithelium. This loss is inversely correlated with tumor grade (Gleason score) and total loss has been observed in metastatic prostate cancer lines [61,62]. Ephrin typr A receptor (EphA4) is down-regulated in invasive forms of breast cancer [99], in liver and kidney cancers [64] and in metastatic melanoma [65]. It has also been suggested that the expression of neogenin may be inversely correlated with malignancy in breast cancer [66]. Consistent with a tumor suppressor function, Notch3 is as also downregulated in breast cancer and this loss is associated with poor survival [67,68].
Overall, the association of these recently identified DRs with tumorigenesis is suspected, however, in most cases, animal models are lacking in order to demonstrate this role.
How to overwhelm tumor suppressors to foster cancer progression
Tumors have thus developed selective advantages to inactivate the natural tumor suppressive activity of DRs, and it was therefore speculated that tumor cells may also overwhelm DRs by producing larger amounts of ligand, conferring cancer cells with the ability to survive independently of ligand limitation and to increase “positive signaling”. Consistently, a growing body of evidence indicates that this "gain of ligand" occurs in many tumors, and is more particularly described for netrin-1, NT-3, SHH, Sema-3E, DKK-1 and Jagged-1.
In line with the first discoveries on DCC and cancer progression, the confirmation that a gain of ligand is associated with tumor progression was first obtained with DCC’s ligand netrin-1. Indeed, the ectopic expression of netrin-1 in the intestinal tract of mice was accompanied by a net decrease in epithelial apoptosis, and these mice had a significant increase in the development of spontaneous focal hyperplasia and adenomas. Moreover, when backcrossed with an APC mutant background, the mice developed more adenocarcinoma [69]. Netrin-1 is overexpressed in a large fraction of cancers [42,70-72], and this overexpression is associated with a poor prognosis in patients with poorly differentiated pancreatic adenocarcinoma [73]. In breast cancer, netrin-1 is correlated with the aggressiveness of the disease and especially with its metastatic potential. An experimental silencing of netrin-1 in various cancer cell lines showed that netrin-1 is associated with cell death in vitro and with tumor growth and metastasis inhibition in mice [74,75]. In vitro cell death and tumor growth inhibition in vivo were also observed when agents interfering the netrin-1/receptor binding were used [74-76], supporting the view that inhibition of netrin-1/DR interaction could be a promising therapeutic strategy. Mechanistically, the pathways underlying netrin-1 up-regulation remain largely unknown, though several studies have proposed diverse routes [76-81].
Neurotrophin-3 (NT-3), ligand of TrkC, is overexpressed in a large fraction of advanced neuroblastoma, and this overexpression blocks the pro-apoptotic activity of TrkC in vitro in human neuroblastoma cell lines [82]. In addition, NT-3 silencing or the inhibition of NT-3/TrkC interaction via an antibody inhibits tumor growth and metastatic spread of human neuroblastoma in xenograft models in chicken and mice [82].
Sonic Hedgehog (SHH) is up-regulated in many cancers in an autocrine and paracrine manner [83,84]. Initially this overexpression was associated with activation of the so-called canonical pathway involving the activation of Gli transcription factors via smoothened (Smo). Nevertheless, while a potent inhibitor of the canonical pathway, the Smo antagonist, GDC-0449, has shown a beneficial effect in patients with basal cell carcinomas or medulloblastomas presenting activating mutations of the PTCH-1-Smo-Gli pathway, this drug has no effect in other tested cancers, even though patients were stratified according to SHH expression. Hence, SHH signaling was suggested to be more complex, involving its DR(s), by blocking their pro-apoptotic activity (especially CDON) [7]. Preclinical models demonstrated that inhibition of SHH/CDON interaction by a SHH titration (SHH-TRAP) could efficiently engage CDON-induced tumor cell death and could potentially benefit patients with tumors expressing SHH [7].
Semaphorin 3E (Sema-3E), ligand of the PlexinD1 receptor, is overexpressed in a large number of cancers, and most often associated with tumor progression. The expression of Sema-3E is associated with the metastatic capacity of ovarian, colon and melanoma cancers, and is correlated with poor survival of patients with colorectal and pancreatic cancers [85-87]. Sema-3E was initially identified as a gene expressed in metastatic breast adenocarcinoma cell lines, whereas it was expressed in only 30% of non-metastatic cell lines [88,89]. The pro-tumoral function of Sema-3E in cancer is controversial, as its overexpression in some models resulted in a decrease in neo-angiogenesis and a reduction in tumor growth [86,87,90], but overexpression of the Sema-3E cleavage fragment by furins contributed to tumor invasion and distant metastasis formation [86,87,91,92]. Since unveiling PlexinD1 as a DR, novel insight into the role of Sema-3E/PlexinD1 in cancer has been gained. Indeed, the autocrine production of Sema-3E was shown to increase the survival of breast cancer cell lines by inhibiting PlexinD1-activated pro-apoptotic signaling. Consequently, the use in preclinical models of TRAP, blocking the Sema-3E/PlexinD1 interaction, led to inhibition of tumor growth and metastasis [8].
The Dickkopf-1 (DKK-1) ligand of Kremen-1 is up-regulated in a number of cancers [93] and this over expression is correlated with poor prognosis [94-100]. Moreover, DKK-1 expression is correlated with cancer aggressiveness in myeloma patients [101]. Paradoxically, this overexpression was perceived as counter-intuitive as up-regulation of DKK-1 should be associated with inhibition of the Wnt pathway, a pro-oncogenic pathway. Once again, its implication as a DR ligand clarified this paradoxical overexpression [17]. Of interest, although not in the context of its role as a DR ligand, DKK-1 inhibition by either knock down or anti-DKK-1 antibodies approaches was considered as a potential cancer therapeutic strategy in a large panel of cancers [93,102]. Sato et al. showed that interference with DKK-1 with an anti-DKK-1 antibody could limit lung tumor growth in vivo and this was accompanied by extensive cancer cell death [93]. Furthermore, the use of an anti-DKK-1 antibody inhibited metastasis of osteosarcoma or of hepatocellular carcinoma in xenograft mice models [102,103] or multiple myeloma dissemination in immunodeficient mice transplanted with relevant organs of the human immune system (SCID-hu mice) [104].
Transposing a recently discovered concept to treat patients with advanced solid cancer
Based on the findings presented above, our team dedicated a significant workforce to transfer our fundamental/preclinical results into a clinical application interfering with ligand/DR interaction, in our case netrin-1/receptors. In effect, an anti-netrin-1 antibody was generated and showed some interesting anti-cancer activities in pre-clinical models [81,105]. This antibody was humanized and has been through all the regulatory preclinical stages. A phase 1 clinical trial launched in 2017 encompassing 60 patients with advanced solid tumors is ongoing (https://clinicaltrials.gov/ct2/show/NCT02977195), and although it is too soon to conclude on the benefits of the anti-netrin-1 mAb, our preliminary data recently reported at ESMO (Cassier et al., Annal of Oncology, 2019) show an excellent safety profile with no dose-limiting toxicity and few adverse effects (i.e. mainly infusion-related reaction commonly seen for humanized antibodies). More importantly and even though next steps will be to explore more specifically target patients that may respond to the treatment, and to investigate whether combination treatments with standards-of-care such as chemotherapy and immunotherapy increase overall patient survival, we have seen some clear signs of clinical activity in patients with advanced cancers. It includes patients showing long-term disease stabilization (>18 months of treatment) or even objective response (shrinking of over 50% of tumoral lesions) (Figure 4). This supports the view that the dependence receptor concept may in the future provide promising solutions for the wellbeing of patients.
Acknowledgements
The authors thank the members of Dependence receptors, Cancer and Development Laboratory for their advice and contribution.
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Figure legends
Figure 1. The Dependence receptor paradigm.
a) Positive signaling. Ligand bound dependence receptor can trigger various survival signals such as differentiation, migration or proliferation. b) Negative signaling. In the absence of its ligand, the dependence receptor induces cell death in an active manner.
Figure 2. Signaling of cell death by dependence receptors
Simplified view of how DRs triggers caspase dependent cell death
Figure 3. Escape of tumor cells by bypassing the survival dependence to dependence receptors.
a) Tissue homeostasis. In a limited ligand environment, aberrant proliferation is controlled by dependence receptors, which induce cell death when unbound by their specific ligands. Tumor escape can be achieved by the silencing of pro-apoptotic pathways (b)), either by the loss of the dependence receptors at the cell membrane (c) or (d) by ligand upregulation in an autocrine (by the cell itself) or paracrine (by other surrounding cells) manners.
Figure 4. Preliminary data on the phase 1 trial assessing the anti-netrin-1 mAb.
Efficacy of the netrin-1 mAb treatment in patients treated in the NP137 trial. a. Evolution of the RESIST (Response Evaluation Criteria in Solid Tumours) lesions in patient 01-10 (advanced cervical cancer) before (0) and upon treatment with NP137 (netrin-1 mAb), showing reduction of the target lesions. b. CT-scan before (Baseline) and after 2 cycles of treatment with the NP137 in patient 02-04 (endometrium adenocarcinoma).