Klotho _ LRP-6 _ Gastric Adenocarcinoma

January 29, 2023 updated by: Marina Bassem Youssef Kostandy, Assiut University

Expression of Klotho and LRP-6 Proteins in Gastric Adenocarcinoma, is it an Important Issue??

Gastric cancer is the fifth most common malignancy in the world after cancers of the lung, breast, colorectum, and prostate. Gastric cancer is the third leading cause of cancer death and is responsible for 723,000 deaths yearly. Gastric carcinoma (GC) is a multifactorial disease which is difficult to diagnose in early-stage because of a time lag between the onset of growth and the appearance of clinical presentation. So, its prognosis is poor as evidenced by the 5-year survival rate.

Klotho is anti-aging gene encoding a protein with multiple pleiotropic effect. Cancer and ageing share comparable principles.

Klotho gene has been described as a tumor suppressor gene in numerous solid tumors and hematological malignancies. Klotho expression has been shown to be significantly down-regulated in malignant tissue compared to adjacent non-malignant tissue with good prognosis in cancers with high Klotho expression, including colorectal, pancreatic, gastric, esophageal, breast, hepatocellular, ovarian, and renal carcinomas. In contrast, a recent study documented that Klotho negative invasive duct carcinoma group exhibited good prognosis than the Klotho positive group regarding the disease- free survival after the surgical resection in breast cancer patient.

Lipoprotein receptor- related protein 6 (LRP6) is a type I single transmembrane protein which is a member of the low-density lipoprotein receptor (LDLR) gene family of receptors that is highly conserved among species. In 2000, LRP6 was identified as a co-receptor for Wnt and Frizzled (FZD) to transduce Wnt/β-catenin signaling. Dysregulation of LRP6 is involved in cancer. LRP6 is highly expressed in several cancer cell lines and overexpression of LRP6 promotes cancer cell proliferation. LRP6 expression is frequently upregulated in breast cancer tissue, and respective overexpression or knockdown of LRP6 induces or inhibits breast tumorigenesis. LRP6 is highly expressed in tumors of liver cancer patients, and overexpression of LRP6 promotes liver cancer cell proliferation and tumor growth. In prostate cancer, high expression levels of LRP6 are detected which activate Wnt/β-catenin signaling and glycolysis through Akt signaling. The end result is increased prostate cancer cell proliferation.

The mechanism of Klotho-mediated Wnt inhibition was as a result of Klotho binding to Wnt ligands, namely Wnt3A and Wnt5A; thereby impeding binding of these ligands to their cell surface receptor.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Gastric cancer is the fifth most common malignancy in the world after cancers of the lung, breast, colorectum, and prostate. Gastric cancer is the third leading cause of cancer death and is responsible for 723,000 deaths yearly [1]. Gastric carcinoma (GC) is a multifactorial disease, where many factors can influence its development, both genetic and environmental such as infection with Helicobacter pylori (which is the main risk factor), gastric ulcer disease, gastroesophageal reflux disease and obesity [2]. Furthermore, genetic variations in proinflammatory and anti-inflammatory cytokine genes also influence the individual response to carcinogenic exposures. Host genetic factors are emerging as key determinants of disease risk for many cancers [1].

Gastric carcinoma is difficult to diagnose in early-stage because of a time lag between the onset of growth and the appearance of clinical presentation. Early symptoms of gastric cancer are not specific; as a result, most patients with early gastric cancer present with symptoms indistinguishable from benign peptic ulcer disease and, subsequently, these patients have been diagnosed at an advanced stage GC [1]. So, its prognosis is poor as evidenced by the 5-year survival rate and because most cases are already metastatic when diagnosed [2]. GC mostly affects older people. The average age of people when they are diagnosed with gastric cancer is 68 years [1].

Klotho is anti-aging gene encoding a protein with multiple pleiotropic effects, discovered in 1997 by Kuro-o and colleagues. The Klotho family of proteins consists of three members: α-Klotho, β-Klotho and γ-Klotho. All three are single-pass transmembrane proteins. The α-Klotho gene is composed of five exons, in humans, mice and rats expressed predominantly in the distal convoluted tubule (DCT) cells of the kidney in addition to a lesser expression in the proximal convoluted tubule (PCT) cells [3].

Cancer and ageing share comparable principles; the time-dependent accumulation of DNA damage is a contributing factor in ageing and also drives cancer progression. DNA damage, alongside genomic instability, is an established hallmark of most cancers. These pathways influence a number of capabilities acquired by cancer cells including the ability to evade apoptosis, cause tumor invasion and metastasis, sustain angiogenesis, and facilitate unlimited cellular replicative potential. Alpha-Klotho potentially influences these phenotypes through the inhibition of a number of signaling pathways such as insulin-like growth factor 1 receptor (IGF-1R), fibroblast growth factor (FGF), transforming growth factor β (TGFβ) and wingless-related integration site (Wnt) [4].

Klotho gene has been described as a tumor suppressor gene in numerous solid tumors and hematological malignancies, Klotho represents a possible therapeutic target for patients with these diseases, the majority of whom have limited treatment options [5].

Klotho expression has been shown to be significantly down-regulated in malignant tissue compared to adjacent non-malignant tissue with good prognosis in cancers with high Klotho expression, including colorectal [6], pancreatic [7], gastric [8], esophageal [9], breast [10], hepatocellular [11], ovarian [12], and renal carcinomas [13]. In contrast, a recent study done by Suzuki et al, 2021 documented that Klotho negative invasive duct carcinoma group exhibited good prognosis than the Klotho positive group regarding the disease- free survival after the surgical resection in breast cancer patient [14].

Lipoprotein receptor- related protein 6 (LRP6) is a type I single transmembrane protein which is a member of the low-density lipoprotein receptor (LDLR) gene family of receptors that is highly conserved among species. In 2000, LRP6 was identified as a co-receptor for Wnt and Frizzled (FZD) to transduce Wnt/β-catenin signaling. The extracellular domain of LRP6 interacts with Wnt and activates Wnt/β-catenin signaling at the plasma membrane. LRP6 with a truncated extracellular domain is constitutively active and can potentiate Wnt/β-catenin signaling independently of Wnt. Dysregulation of LRP6 is involved in cancer. LRP6 is highly expressed in several cancer cell lines and overexpression of LRP6 promotes cancer cell proliferation [15].

LRP6 expression is frequently upregulated in breast cancer tissue, and respective overexpression or knockdown of LRP6 induces or inhibits breast tumorigenesis [16]. LRP6 is highly expressed in tumors of liver cancer patients, and overexpression of LRP6 promotes liver cancer cell proliferation and tumor growth [17]. In prostate cancer, high expression levels of LRP6 are detected which activate Wnt/β-catenin signaling and glycolysis through Akt signaling. The end result is increased prostate cancer cell proliferation [19].

The mechanism of Klotho-mediated Wnt inhibition was as a result of Klotho binding to Wnt ligands, namely Wnt3A and Wnt5A; thereby impeding binding of these ligands to their cell surface receptor [4].

Klotho has also been shown to increase the efficacy of chemotherapy, including cisplatin in human lung cancer by modulating the phosphatidylinositol 3-kinase/protein kinase B PI3K/Akt pathway, indicating that Klotho therapy may be effective in combination with existing cancer therapies [4].

To our knowledge, it is the first research to study the expression of Klotho and LRP-6 protein in gastric adenocarcinoma by immunohistochemistry.

Study Type

Observational

Enrollment (Anticipated)

45

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The study is retrospective cohort study of 40-50 cases of gastric adenocarcinoma in our South Egypt Cancer Institute in the period from 2016 to 2020.

Description

Inclusion Criteria:

  • Patients had a pathological diagnosis of gastric adenocarcinoma.
  • Staging, lymph node (LN) metastasis and overall survival (OS) were analyzed according to Klotho and LRP-6 expression status.

Exclusion Criteria:

  • Gastric Tumors other than adenocarcinoma.
  • Cases with loss records files.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Klotho

Evaluate the expression of Klotho in gastric adenocarcinoma via immunohistochemistry, find the association between the expression of Klotho in gastric adenocarcinoma and demographic patient data, and clinicopathologic parameters of the patients and investigate the effect of Klotho expression on the prognosis of gastric adenocarcinoma.

Correlate between the Klotho and LRP-6 protein expression.
Other: Prognostic study
No intervention... as it is a prognostic study and no intervention done on patients.
LRP-6

Evaluate the expression of LRP-6 protein in gastric adenocarcinoma via immunohistochemistry, find the association between the expression of LRP-6 protein in gastric adenocarcinoma and demographic patient data, and clinicopathologic parameters of the patients and investigate the effect of LRP-6 protein expression on the prognosis of gastric adenocarcinoma.

Correlate between the Klotho and LRP-6 protein expression.
Other: Prognostic study
No intervention... as it is a prognostic study and no intervention done on patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Expression of Klotho and LRP-6 proteins in gastric adenocarcinoma
Time Frame: 1-2 years
Expression of Klotho and LRP-6 proteins in gastric adenocarcinoma via immunohistochemistry.
1-2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assiut University

Collaborators

South Egypt Cancer Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

April 1, 2023

Primary Completion (Anticipated)

April 1, 2024

Study Completion (Anticipated)

April 1, 2024

Study Registration Dates

First Submitted

March 11, 2022

First Submitted That Met QC Criteria

March 19, 2022

First Posted (Actual)

March 24, 2022

Study Record Updates

Last Update Posted (Actual)

January 31, 2023

Last Update Submitted That Met QC Criteria

January 29, 2023

Last Verified

January 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Klotho _ LRP-6 _ GC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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