AUTHOR=Kleczko Emily K. , Poczobutt Joanna M. , Navarro Andre C. , Laskowski Jennifer , Johnson Amber M. , Korpela Sean P. , Gurule Natalia J. , Heasley Lynn E. , Hopp Katharina , Weiser-Evans Mary C.M. , Gottlin Elizabeth B. , Bushey Ryan T. , Campa Michael J. , Patz Edward F. , Thurman Joshua M. , Nemenoff Raphael A. TITLE=Upregulation of complement proteins in lung cancer cells mediates tumor progression JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2023 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.1045690 DOI=10.3389/fonc.2022.1045690 ISSN=2234-943X ABSTRACT=Introduction

In vivo, cancer cells respond to signals from the tumor microenvironment resulting in changes in expression of proteins that promote tumor progression and suppress anti-tumor immunity. This study employed an orthotopic immunocompetent model of lung cancer to define pathways that are altered in cancer cells recovered from tumors compared to cells grown in culture.

Methods

Studies used four murine cell lines implanted into the lungs of syngeneic mice. Cancer cells were recovered using FACS, and transcriptional changes compared to cells grown in culture were determined by RNA-seq.

Results

Changes in interferon response, antigen presentation and cytokine signaling were observed in all tumors. In addition, we observed induction of the complement pathway. We previously demonstrated that activation of complement is critical for tumor progression in this model. Complement can play both a pro-tumorigenic role through production of anaphylatoxins, and an anti-tumorigenic role by promoting complement-mediated cell killing of cancer cells. While complement proteins are produced by the liver, expression of complement proteins by cancer cells has been described. Silencing cancer cell-specific C3 inhibited tumor growth In vivo. We hypothesized that induction of complement regulatory proteins was critical for blocking the anti-tumor effects of complement activation. Silencing complement regulatory proteins also inhibited tumor growth, with different regulatory proteins acting in a cell-specific manner.

Discussion

Based on these data we propose that localized induction of complement in cancer cells is a common feature of lung tumors that promotes tumor progression, with induction of complement regulatory proteins protecting cells from complement mediated-cell killing.