Year: 2007
Type: article
Abstract: It is generally accepted that human cancer is a result of genetic mutations in molecular pathways controlling processes that normally harness the capacity for proliferation and survival. An emerging picture has begun to evolve from our understanding of these particular pathways as they become disrupted in various cancers, in a fashion which shows significant lineage-dependence. Cutaneous malignant melanoma, the most common form of melanoma in man, appears to invariably harbor mutations leading to activation of the canonical MAPK-pathway wherein the oncogene BRAF is found activated in approximately 70% of all melanomas (Davies et al., 2002) as well as benign nevi (Pollock et al., 2003) and correspondingly NRAS in another ∼25% (Demunter et al., 2001) leaving only a small fraction unaccounted for. In addition, disruption of the pRB-pathway through loss of pRB, mutation or amplification of CDK4, amplification of CCND1, missense mutation or deletion of the INK4A-locus is similarly common. However, contrasting many other human malignancies, melanomas exhibit a strikingly low frequency of canonical p53-mutations, amounting to approximately 20–25% of all cases (Ragnarsson-Olding et al., 2002). This is particularly notable because of the discordance between the p53's wild-type status and the near-uniform relative refractoriness of melanomas to numerous triggers of apoptosis, including cytotoxic chemotherapeutic agents. Additionally, disruption of the TP53-pathway through amplification of the HDM2 oncogene occasionally occurs, but its upstream inhibitor ARF, the alternative product of the INK4A-locus (Kamijo et al., 1997), is a well-known melanoma tumor-suppressor whose loss together with CDKN2A/p16 is relatively common during melanoma-genesis. It is broadly accepted that ARF functions to inhibit MDM2/HDM2, the canonical negative regulator of p53, in mouse and man while there are additional ARF-interacting proteins that may execute important functions various settings of tumorigenesis (Sherr, 2006). The common occurrence of wild-type p53 together with ARF (and CDKN2A/p16) deficiency in melanoma has appropriately raised the prospect of a therapeutic opportunity based upon reactivating p53-function, to which end multiple lead drugs are in various stages of development. In a recently published study, Merlino and colleagues (Ha et al., 2007) have utilized a powerful genetic model of murine melanoma to assess the functional roles of p53 and ARF in murine melanoma-genesis. Their data clearly demonstrate p53-independent tumor suppressive activity of ARF- an observation which carries important implications for therapeutic targeting/activation of p53 in melanoma patients. In this study, Ha et al. employ an established mouse model that develops UV-induced cutaneous melanoma as well as rhabdomyosarcoma (RMS) via transgenic expression of hepatocyte growth factor/scatter factor (Noonan et al., 2001), the ligand for the cMET receptor tyrosine kinase. Merlino et al. previously showed that melanoma latency following UV irradiation was significantly reduced when the transgenic mice were crossed into an INK4A/ARF-null background, suggesting that loss of both the TP53- (through ARF) and pRB- (through CDKN2A/p16) pathways likely contribute to development of UV-induced cutaneous melanoma. In this study, the authors have overlaid a more refined approach, of separating the functions of the two products from the INK4A-locus. They observe that ARF-nullizygosity exhibits nearly the same frequency and timing of RMS development as genetic ablation of both products. Similarly, p53-nullizygousity exhibited similar frequency and timing as ARF-alone for induction of RMS, thus consistent with the predicted role of the ARF-(MDM2)-p53-pathway for tumor suppression. Importantly, however, UV-induced melanoma incidence in these transgenic animals showed dependence on both CDKN2A and ARF status whereas p53-nullizygousity had no overt effect, suggesting that ARF tumor suppressor function is mechanistically distinct from p53-function. The importance of this melanoma-specific behavior is underscored by the differences seen in RMS tumors within the same genetic model. Interestingly, in a UV-independent RAS-driven transgenic model, CDKN2A, ARF and p53 all displayed important contributions as suppressors of melanoma incidence (Bardeesy et al., 2001; Sharpless and Chin, 2003). Exposing the RAS-driven melanoma model to UV in the absence of ARF accelerated melanoma development via mutational events in the pRB-pathway (Kannan et al., 2003). Importantly, this new study suggests an important and specific relationship between ARF as a suppressor of UV-dependent acceleration of carcinogenesis. What phenotypic role(s) might ARF play in suppressing tumorigenesis? Ha et al. demonstrate a powerful role for ARF in triggering cellular senescence which is also genetically independent of p53 (Figure 1). Moreover the authors show that oncogenic NRAS cooperates with ARF loss to transform mouse melanocytes, whereas TP53 shRNA knock-down did not cooperate, in a CDKN2A-null background. In addition, re-expression of ARF in CDKN2A-ARF null melanocytes led to induction of hallmarks of senescence; SA-β-Gal staining and phospho-HP1γ induction, in a manner independent of TP53 status. Schematic view of the INK4A-ARF-locus with its control of downstream tumor-suppressor pathways and input from specific stress inducers. This role of ARF as an inducer of senescence offers an interesting and plausible explanation for the observation that nevi exhibit senescence-like features (Michaloglou et al., 2005). Genetic loss or mutation of ARF-function (or perhaps silencing) might thus permit evasion of senescence following NRAS/BRAF missense mutations and contribute to progression beyond benign nevi in the spectrum of melanocyte-associated neoplasias. The imperfect correlation between CDKN2A/p16 suppression and the senescent phenotype in nevi (Michaloglou et al., 2005) is consistent with this possibility. Collectively, the study by Ha et al. (Ha et al., 2007) argues strongly for an important TP53-independent function of ARF in melanoma tumor suppression involving regulation of senescence, an irreversible state thought to represent a major barrier to tumourigenesis in man. This study emphasizes the value of applying a genetically defined model system to the analysis of melanoma-genesis, as it generates precious clues to the etiology of the disease in man. Outstanding questions include the identification of the senescence effector(s) downstream of ARF, potentially involving E2F1, as described by Ha et al. The possible interaction of ATR/ATM and ARF is interesting in this regard given the UV-dependence of the observed effects. As pointed out by the authors, the therapeutic importance of these findings may well apply to the utility (or lack thereof) of p53-activating strategies in advanced melanoma. Although humbling as a potential barrier to that clinical approach, the identification of ARF's p53-independent activity should be viewed as the first step towards elucidation of a functionally critical pathway which will hopefully offer new and potent therapeutic strategies in the future.
Source: Pigment Cell Research
Authors: Hans R. Widlund, David E. Fisher
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1972531956