A growing challenge in medicine today, is the need to improve the suitability of drug treatments for cancer patients. In this field, biomarkers have become the “flags” to provide additional ...information in tumor biology. They are a relay between the patient and practitioner and consequently, aid in the diagnosis, providing information for prognosis, or in some cases predicting the response to specific therapies. In addition to being markers, these tumor “flags” can also be major participants in the process of carcinogenesis.
Neurotensin receptor 1 (NTSR1) was recently identified as a prognosis marker in breast, lung, and head and neck squamous carcinomas. Neurotensin (NTS) was also shown to exert numerous oncogenic effects involved in tumor growth and metastatic spread. These effects were mostly mediated by NTSR1, making the NTS/NTSR1 complex an actor in cancer progression. In this review, we gather information on the oncogenic effects of the NTS/NTSR1 complex and its associated signaling pathways in order to illuminate its significant role in tumor progression and its potential as a biomarker and a therapeutic target in some tumors.
► Biomarkers act as relays between patients and practitioners. ► They help define the diagnosis, the prognosis, and to condition patient therapies. ► NTS/NTSR1 exerts a significant role in tumor progression. ► NTS/NTSR1 is a potential biomarker for tumor aggressiveness.
Glucocorticoids (GCs) regulate cell homeostasis and can affect carcinogenesis. An inherited germline mutation in the BRCA1 gene, a tumor suppressor gene, confers a predisposition to breast and ...ovarian cancers. BRCA1 participates in the maintenance of genome stability through DNA repair, in cellular homeostasis through gene transcription, and in signaling regulation. The interaction between BRCA1 and the glucocorticoid receptor (GR) signaling pathway was studied in normal breast tissues and triple-negative breast cancers from
BRCA1
mutation carriers. A loss of the active Ser211 phosphorylated form of GR was found in the mutant as compared to the non-mutant. In in vitro studies, the
BRCA1
status in breast cancer cell lines regulates GC-dependent proliferation/apoptosis and impacts GC-dependent gene expression. The lack of BRCA1 inhibited dexamethasone actions on its target genes’ expression and the opposite effect was seen with BRCA1 overexpression. BRCA1 overexpression enhances MAPK p38 phosphorylation, resulting in an amplification of GR phosphorylation on Ser 211 and GR basal expression. Our results indicate that BRCA1 is essential to develop an efficient GC signalization. GR P-Ser211 levels may constitute an important diagnostic factor for screening BRCA1 loss of expression in tumors from
BRCA1
mutation carriers as well as in sporadic BRCAness tumors. This marker may help to optimize therapeutic strategies.
A present challenge in breast oncology research is to identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in ...20% of breast cancers, and NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in invasive breast carcinomas. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here, we depict the cellular mechanisms activated by NTS, and contributing to breast cancer cell aggressiveness. We show that neurotensin (NTS) and its high affinity receptor (NTSR1) contribute to the enhancement of experimental tumor growth and metastasis emergence in an experimental mice model. This effect ensued following EGFR, HER2, and HER3 over-expression and autocrine activation and was associated with an increase of metalloproteinase MMP9, HB-EGF and Neuregulin 2 in the culture media. EGFR over expression ensued in a more intense response to EGF on cellular migration and invasion. Accordingly, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, as well as metformin, reduced the tumor growth of cells overexpressing NTS and NTSR1. All cellular effects, such as adherence, migration, invasion, altered by NTS/NTSR1 were abolished by a specific NTSR1 antagonist. A strong statistical correlation between NTS-NTSR1-and HER3 (p< 0.0001) as well as NTS-NTSR1-and HER3- HER2 (p< 0.001) expression was found in human breast tumors. Expression of NTS/NTSR1 on breast tumoral cells creates a cellular context associated with cancer aggressiveness by enhancing epidermal growth factor receptor activity. We propose the use of labeled NTS/NTSR1 complexes to enlarge the population eligible for therapy targeting HERs tyrosine kinase inhibitor or HER2 overexpression.
Summary Clusterin (CLU) is a sulfated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. Several studies have reported the overexpression of CLU in ...human neoplasm, examined by immunohistochemistry. However, there is no extensive data on its role in the thyroid. Here we investigate CLU expression in thyroid tumors, and the potential correlation between this expression and clinicopathologic parameters. Immunohistochemistry with Anti-CLU was performed on paraffin sections from 39 thyroid tumors. Only medullary thyroid carcinomas (MTC) were positive (n=5). To confirm these results, 130 further cases (including 4 C-Cell hyperplasia), their matched lymph node metastases (46 cases) and lymph node recurrences (10 cases) were analysed. All MTCs were subdivided according to WHO classification. Cytoplasmic positivity was scored qualitatively (weak, moderate, strong) and quantitatively on a 5-tier scale from 0, 1+ (less than 10% of cells positive) to 5+ (more than 75%). Statistical analysis was performed. CLU was expressed in normal C-cells, C-cells hyperplasia, all MTCs, their lymph node metastases, and recurrences. There was a strong association between CLU score and the cellular type (P<0.004). CLU score was inversely correlated with the presence of lymph node metastases (P<0.0001). There were no differences between primary and metastatic or recurrent tumors. CLU expression is related to the cellular type and inversely correlated with the presence of lymph node metastases, which could represent a new positive prognostic factor.
Metastasis to the adrenal glands is a relatively frequent finding at autopsy. Adrenal metastasis of colorectal carcinoma is rare (14 percent). Isolated adrenal metastasis is even rarer, and presents ...a therapeutic dilemma.
Between 1997 and 2006, eight patients (5 men; mean age, 62 years) underwent adrenalectomy for metastasis of colorectal carcinoma. The tumors were Stage D in four cases, Stage B in two cases, and Stage C in the remaining two. Adjuvant chemotherapy was instituted.
All patients were asymptomatic, and adrenal metastasis was suspected from an elevated serum level of carcinoembryogenic antigen or discovered by computed tomography. Adrenal metastases were metachronous in seven patients, with median disease-free interval of 3.75 years. At the time of follow-up, one patient remained alive and free of disease 12 months after adrenalectomy, one patient was lost to follow-up after 22 months, and 6 patients have died from malignancy. The mean survival for the patients who died was 32 months.
The rarity of isolated adrenal metastasis of colorectal carcinoma makes a randomized, prospective trial comparing surgery vs. nonsurgical management highly unlikely. Our results provide further support for surgical resection of solitary adrenal metastasis, which may translate into survival benefit.
Multicystic schwannoma of the porta hepatis Mourra, Najat; Colignon, Nikias; Zaatari, Ghazi
Clinics and research in hepatology and gastroenterology,
September 2020, 2020-09-00, 20200901, Volume:
44, Issue:
4
Journal Article
Several genes have been recognized, when mutated in the germline, to highly predispose to colorectal cancer, impairing the DNA mismatch repair system in hereditary nonpolyposis colon cancer syndrome, ...or APC/MYH in adenomatous polyposis. However, 10 percent of microsatellite stable colorectal cancer is reported to develop in an unexplained context of genetic predisposition. This study was designed to depict the genetic mechanisms underlying early-onset microsatellite stable colon cancers.
Patients younger than aged 50 years undergoing primary surgical resection for colon carcinoma were collected prospectively between 1993 and 2003. A first series of 8 samples has been allelotyped using 361 poly-CA polymorphisms distributed on the 39 autosomal arms within a larger set of 166 sporadic tumors. Genotyping of 24 poly-CA polymorphisms distributed on the 8 chromosomes exhibiting allelic losses in more than 30 percent of the previous cases was then applied to an independent series of 40 tumors. A third series of 70 tumors has been genotyped on chromosome 14 only.
Comparison of genomic profile from patients younger and older than aged 50 years at the 8 most frequently lost chromosomes allowed, identify chromosome 14 as showing a significant difference between the two groups. Dense chromosome 14 genotyping detected two partial deletions in a general background of 57 percent allelic loss, pointing at a region located between D14S63 and D14S292.
These observations suggest that a tumor-suppressor gene located on chromosome 14 might have an important role in microsatellite stable colon carcinogenesis. Because it seems to be more frequently involved in early-onset cases, it could be a good candidate in inherited conditions.