Gynaecological cancer and chemoresistance
Ovarian Cancer (OC) is the fifth most common cancer in women and is the leading cause of death among the female genital tract malignancies. The high mortality rate of ovarian carcinoma is partly due to the fact that more than 70% of cases are detected at an advanced stage and partly because the current chemotherapeutic regimes (particularly the use of cisplatin) are ineffective due to the development of chemoresistance. The 5-year survival rate of these OC women is only 20–30%. Although there is controversy concerning the possible oviductal or ovarian surface epithelium origin of ovarian cancer, more than 85% of OC are of epithelial origin. As for endometrial Cancer (EC), it is currently the leading type of gynecological cancer and is 4th in importance among all types of cancers in women (Canadian Cancer society and NIH USA statistics, 2014). Patients with tumor confined to the uterus are treated with surgery and radiotherapy; however, more than 25% of patients diagnosed with EC have an invasive primary tumor accompanied by regional and/or distant metastases. Current chemotherapeutic agents for EC include cisplatin and doxorubicin (adriamycin; doxorubicin). These drugs are efficient single agents, and when used in combination, the compounds show an increased effect. Chemoresistance, however, represents a major cause of treatment failure. Even though patients are treated with aggressive chemotherapeutic regimens, recurrent EC cases have a 5-year survival rate of less than 20%. Together, OC and EC represent a crucial health problematic and it is imperative that we identify novel therapeutic strategies to treat these chemoresistant gynecological cancers.
Recognition and maintenance of pregnancy is a complex process involving both maternal and embryonic signals. The failure to establish a communication between embryo and uterus has been shown to be the most important cause of infertility among mammals. In the rodents, trophoblast cells (the outer membrane of the embryo) come into close apposition with endometrial epithelium during early implantation, and epithelial cells undergo apoptosis.
Later during pregnancy, stromal cells undergo decidualization, involving controlled proliferation, followed by decidua basalis regression, involving apoptosis of decidual cells. It is generally accepted that apoptosis of endometrial epithelial cells plays an important role in implantation and that apoptosis is also the mechanism by which decidua basalis regresses, but molecular mechanisms governing endometrial cell apoptosis are not yet defined.
The Akt isoforms
The pro-survival role of Akt has been demonstrated in multiple cell lines. The molecule responsible for recruitment of Akt to the cellular membrane and its subsequent activation is the lipid kinase PI3-K. PI3-K has been found to be an important signaling molecule for several growth factor receptors in a variety of cell types. Upon activation, PI3-K induces Akt phosphorylation, which phosphorylates and blocks the action of Bad, a pro-apoptotic member of the Bcl-2 family and alters the activity of a number of other apoptosis regulators, including caspase-9 and NF-kB. In EC tumours, frequency of mutation in PTEN tumour suppressor gene (phosphatase and tensin homologue deleted on chromosome ten, a negative regulator of PI3-K) is several-fold higher than that described for any other gene, including K-ras and p53, making PTEN mutation the most common genetic alteration identified to date in EC. Genotyping studies indicate that approximately 50% of EC cells harbor a double-allele mutated PTEN gene. For OC, the recent published data from Cancer Genome Atlas Research Network demonstrated an aberrant function/hyperactivation of the PI3-K/Akt pathway in 34% of OC cases and these include mutations in PIK3CA, deletion in PTEN, as well as amplification of Akt1, Akt2, and Akt3, the three distinct Akt isoforms. While their structures are highly similar, their activity can be differentially regulated: for example, a phosphorylation site at thr34 (within the pleckstrin homology domain) has been shown to lead to inactivation of Akt1 by preventing binding to phosphatidylinositol 3,4,5-trisphosphate. On the other hand, Akt2 and Akt3 have a serine at this position, and these isoforms may be phosphorylated and regulated differently; phosphorylation being the central event of their activation. Interestingly, in a recent 2013 manuscript published in Nature, Elaine Fuchs’s lab showed, using a large-scale RNAi screen in mice, that Akt3 was in the top 10 most essential genes for oncogenic growth. In another recent study, Akt1 ablation significantly delays initiation of lung tumor growth, whereas Akt2 and Akt3 deficiencies dramatically accelerated tumorigenesis in the viral oncogene-induced mouse model of lung cancer. Taken together, these study confirms that Akt isoforms are not redundant and may play different roles in cell survival.
The Par-4 tumor suppressor
Par-4, the product of the pro-apoptotic gene Pawr, was originally identified in prostate cancer cells undergoing apoptosis. Since its discovery, Par-4 has been shown to possess apoptotic activity in response to numerous stimuli in various cellular systems. Furthermore, Par-4 knockout (KO) mice show reduced lifespan and enhanced benign tumor formation, particularly in the prostate and endometrium. Approximately, 80% of Par-4 KO females had endometrial hyperplasia and 36% developed EC after one year of age. Importantly, Par-4 levels, which dictate its pro-apoptotic activity and tumor suppressor function, are not solely regulated at the expression level but are also modulated post-translationally, through diverse mechanisms; we have shown very recently that Par-4 is cleaved by caspase-3 during apoptosis induction in many different cancer cells. Par-4 contains a unique core domain (residues 146-203), which induces apoptosis specifically in cancer cells, and therefore is called the SAC domain (Selective for Apoptosis in Cancer cells). Thus, the pro-apoptotic role of Par-4 is cancer cell specific in a manner that overexpression of Par-4 is sufficient to induce apoptosis in most cancer cells but not in normal or non-cancer cells. This selectivity is certainly the most desirable element in cancer therapeutics.
Research conducted in the Asselin Lab
Our lab is involved in many topics of fundamental research; we mainly interest ourselves in deciphering cell fate mechanisms, in both physiological and pathological settings in the context of hormones influence. In order to achieve this, we use an integrated, multi-faceted approach utilizing both cellular and molecular biology methodologies. We are member of a research group, the Research Group in Cellular Signaling, which works on a plethora of subjects, ranging from neurosciences to oncology.
Professor Asselin is a recognized expert in the field of uterine and ovarian cancer as well as reproductive physiology. Owing to his multiple partnership with oncologist and pathologist from both Trois-Rivières hospital and CHUM, we have access to a great number of databases as well as biological samples ranging from biopsies tissue microarrays to patient tumor derived cell-lines.
Our team is very dynamic and hails from all around the world. Each team member is given great autonomy to research goals and develop specific set of skills; our research ideology is for our grad students to generate solid science through skillful and
rigorous training. Combined together, the expertise of all our members allow us to attack each specific problems and questions using a collaborative and synergistic approach.
The role of estrogens in gynecological cancer
The importance of sex steroids in cancer progression has been studied for more than a century. Estrogen (17β-estradiol) has long since been accepted as a potent and fundamental inducer of cancer. Indeed, in 2002, the National Institute of Environmental Health Sciences officially recognized estrogen as an oncogenic substance. The ability of estrogen to induce cancer stems comes from its ability to act as a growth factor in sensitive tissues; many cancers initially require sex steroids to thrive, akin to their organ of origin, until the amassed mutations renders the tumor growth process independent from steroid influence. Unopposed estrogen stimulation on sensitive tissues has been shown to be a primary risk factor for hormone-dependent cancers. Considering both the rising use of estrogen supplementation amongst women, either as a contraceptive or for the treatment of menopause, and the endemic obesity in occidental countries, which is correlated with increased estrogen levels, the treatment and prevention of estrogen-dependent cancers is a critical challenge. It is well established that the endometrium is an exquisitely hormone-sensitive organ; more than ~85% of type 1 endometrial cancer (EC), the most prevalent type of this disease, are estrogens dependent. In Canada and USA, EC is the most prevalent type of gynecological cancer, as well as the fourth most prevalent amongst any other cancer in women. Despite the prominent incidence of EC, the 5-year relative survival rate for afflicted women has not improved since 1975 and patients diagnosed with high-stage tumors still face 5-year survival rates of less than 20%. These statistics are largely attributed to the high incidence of chemoresistance found in recurring tumors. The effects of estrogen as a promoter of cancer progression are increasingly recognized; however, a deeper understanding of the role of estrogens and downstream signaling pathways in chemoresistance is needed to further develop novel therapeutic strategies. In order to achieve this objective, we must first identify estrogen-mediated molecular mechanisms involved in chemoresistance; we must then identify approaches that will capitalize on these original findings and use our enhanced understanding to develop improved treatments of resistant gynecological malignancies.
17β-estradiol (E2) is a well-known promoter of cancer through the activation of proliferation pathways, the inducement of DNA damage, and the transcriptional repression of tumor suppressors, including pro-apoptotic genes. Considering that the loss of apoptotic capacity observed in tumour cells is frequently the consequence of tumor suppressor deletions and/or irreversible mutations that are hard to clinically target, the identification of functionally silenced and/or transcriptionnaly down-regulated pro-apoptotic proteins represent a compelling alternative approach. Indeed, reinstating the aforementioned proteins activity or controlling their transcriptional repression would constitute a promising strategy for cancer treatment.