image: Figure 4: Histological staining reveals Cthrc1 KO alters tumor microarchitecture and cellularity.
Histological sections of mouse tumors from the endpoint study are shown. Tumors from WT and Cthrc1 KO mice at Day 14 post-inoculation were stained with Trichrome (top) and Hematoxylin and Eosin (H&E; bottom). Representative tumors from (A) WT and (B) Cthrc1 KO mice are shown at 40X (left) and 400X (right) magnification. Scale bar, 200 μm. Tumor cellularity per histological sample was scored using a Likert scale as described in Methods and are shown as (C) violin and (D) histogram plots (n = 18 WT, n = 19 Cthrc1 KO). Because the sample size is small and the scores are not normally distributed, differences in cellularity between WT and Cthrc1 KO tumor samples were assessed using a Mann-Whitney U-test. Vli55 immunohistochemical staining of tumor sections at 200X and 400X magnification for (E, F) WT and (G) Cthrc1 KO mice shows the fibrous capsule and tumor tissue, with positive staining for CTHRC1 only in WT tumors. (H) A stained regressed tumor from a Cthrc1 KO mouse shows residual matrix, few fibroblasts, and no CTHRC1. Scale bar, 200 μm. CD31 immunostaining of tumor sections at 200X magnification shows positive vessel-like structures in stroma and tumors of both (I, J) WT and (K, L) Cthrc1 KO mice. Positive staining (dark brown) is marked by arrows.
Credit: Copyright: © 2026 Duval et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“These results identify CTHRC1 as a key driver of CRC that may suppress the immune system, allowing for easier immune evasion by tumor cells, highlighting CTHRC1 as a potential new target for therapy.”
BUFFALO, NY – June 2, 2026 – A new research paper was published in Volume 17 of Oncotarget on May 20, 2026, titled “Microenvironmental CTHRC1 has a pro-tumorigenic role in colorectal cancer.”
The study was led by first author Haylee Duval from the Center for Molecular Medicine at the MaineHealth Institute for Research and the Graduate School of Biomedical Science and Engineering at the University of Maine. The study’s corresponding authors were Sergey Ryzhov, Volkhard Lindner, and Michaela R. Reagan, who are affiliated with the Center for Molecular Medicine at the MaineHealth Institute for Research, the Graduate School of Biomedical Science and Engineering at the University of Maine, and Tufts University School of Medicine.
Colorectal cancer remains one of the leading causes of cancer-related deaths worldwide. While much research has focused on cancer cells themselves, growing evidence suggests that the tumor microenvironment—the network of surrounding stromal cells, immune cells, and extracellular components—plays a critical role in determining how tumors grow and spread.
In this study, researchers investigated collagen triple helix repeat containing 1 (CTHRC1), a secreted protein previously associated with poor outcomes in several cancer types. Although CTHRC1 is frequently detected in tumor-associated stroma, its precise role within the colorectal cancer microenvironment has remained unclear.
To address this question, the team used a genetically engineered mouse model lacking CTHRC1 and compared tumor development with that of normal mice after colorectal cancer cells were introduced. The results consistently showed that the absence of host-derived CTHRC1 significantly reduced tumor growth.
Across three independent experimental cohorts, mice lacking CTHRC1 developed substantially smaller tumors than their normal counterparts. In addition, survival improved markedly. The median survival of mice with normal CTHRC1 expression was 28 days after tumor inoculation, compared with 69 days in CTHRC1-deficient mice.
The researchers also found evidence that CTHRC1 influences anti-tumor immunity. Mice lacking CTHRC1 had higher percentages of CD3-positive T cells in both tumors and spleens, suggesting a more active immune response against cancer. At the same time, they exhibited reduced levels of certain myeloid immune cells associated with immune suppression.
Importantly, the investigators confirmed that the colorectal cancer cells themselves did not produce detectable CTHRC1. Instead, the protein was found primarily in fibroblasts and other stromal components surrounding the tumor. This finding indicates that the tumor-promoting effects originated from the tumor microenvironment rather than from the cancer cells directly.
Histological analyses further revealed striking differences in tumor structure. Tumors from CTHRC1-deficient mice contained fewer cells and showed evidence of regression, while tumors in normal mice remained densely cellular and continued to expand.
“Comparing subcutaneous CRC growth between immunocompetent C57BL/6 and global Cthrc1 null mice revealed significant tumor regression in Cthrc1 KO mice across three independent cohorts.”
The authors propose that CTHRC1 may help create an environment that favors tumor growth by limiting effective immune surveillance. By suppressing anti-tumor immune activity, the protein may allow cancer cells to evade immune defenses and continue proliferating.
Overall, the findings provide the first direct evidence that host-derived CTHRC1 promotes colorectal cancer progression. The study highlights the importance of the tumor microenvironment in cancer development and suggests that targeting CTHRC1 may represent a promising new strategy for future colorectal cancer therapies.
DOI: https://doi.org/10.18632/oncotarget.28878
Correspondence to: Sergey Ryzhov – Sergey.Ryzhov@mainehealth.org; Volkhard Lindner- Volkhard.Lindner@mainehealth.org; Michaela R. Reagan – Michaela.Reagan@mainehealth.org
Keywords: cancer, Cthrc1, CRC, colorectal cancer, subcutaneous tumor model, immune analysis
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Journal
Oncotarget
Method of Research
News article
Subject of Research
Not applicable
Article Title
Microenvironmental CTHRC1 has a pro-tumorigenic role in colorectal cancer
Article Publication Date
20-May-2026
COI Statement
VL holds patents on CTHRC1 antibodies. All others declare no CoIs.