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      Collagen Type XI Alpha 1 (COL11A1): A Novel Biomarker and a Key Player in Cancer

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          Abstract

          Simple Summary

          Collagen type XI alpha 1 (COL11A1) is a part of type XI collagen, which is important for bone development. Interestingly, COL11A1 levels are frequently upregulated in various cancers and high levels of COL11A1 are correlated with poor clinical outcome in many solid cancers. Increasing evidence shows that COL11A1 promotes tumor cell aggressiveness through multiple mechanisms. In this review, we discuss how COL11A1 serves as both a biomarker and a key player in cancer. This knowledge will facilitate the development of novel therapies to treat COL11A1-high cancers.

          Abstract

          Collagen type XI alpha 1 (COL11A1), one of the three alpha chains of type XI collagen, is crucial for bone development and collagen fiber assembly. Interestingly, COL11A1 expression is increased in several cancers and high levels of COL11A1 are often associated with poor survival, chemoresistance, and recurrence. This review will discuss the recent discoveries in the biological functions of COL11A1 in cancer. COL11A1 is predominantly expressed and secreted by a subset of cancer-associated fibroblasts, modulating tumor-stroma interaction and mechanical properties of extracellular matrix. COL11A1 also promotes cancer cell migration, metastasis, and therapy resistance by activating pro-survival pathways and modulating tumor metabolic phenotype. Several inhibitors that are currently being tested in clinical trials for cancer or used in clinic for other diseases, can be potentially used to target COL11A1 signaling. Collectively, this review underscores the role of COL11A1 as a promising biomarker and a key player in cancer.

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          Most cited references118

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          The collagen family.

          Collagens are the most abundant proteins in mammals. The collagen family comprises 28 members that contain at least one triple-helical domain. Collagens are deposited in the extracellular matrix where most of them form supramolecular assemblies. Four collagens are type II membrane proteins that also exist in a soluble form released from the cell surface by shedding. Collagens play structural roles and contribute to mechanical properties, organization, and shape of tissues. They interact with cells via several receptor families and regulate their proliferation, migration, and differentiation. Some collagens have a restricted tissue distribution and hence specific biological functions.
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            Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.

            Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.
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              Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy

              With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGFβ and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15+ CAFs surround tumor islets and are absent from normal pancreatic tissue. The presence of LRRC15+ CAFs in human patients was confirmed in >80,000 single cells from 22 patients with PDAC as well as by using IHC on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising more than 600 patients across six cancer types revealed elevated levels of the LRRC15+ CAF signature correlated with poor response to anti-PD-L1 therapy. This work has important implications for targeting nonimmune elements of the tumor microenvironment to boost responses of patients with cancer to immune checkpoint blockade therapy. SIGNIFICANCE: This study describes the single-cell landscape of CAFs in pancreatic cancer during in vivo tumor evolution. A TGFβ-driven, LRRC15+ CAF lineage is associated with poor outcome in immunotherapy trial data comprising multiple solid-tumor entities and represents a target for combinatorial therapy.This article is highlighted in the In This Issue feature, p. 161.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                24 February 2021
                March 2021
                : 13
                : 5
                : 935
                Affiliations
                Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA; nallans@ 123456amc.edu (S.N.); heiserj@ 123456amc.edu (J.P.H.)
                Author notes
                [* ]Correspondence: cheond@ 123456amc.edu ; Tel.: +1-518-262-2305; Fax: +1-518-262-5669
                Author information
                https://orcid.org/0000-0001-7042-2135
                https://orcid.org/0000-0002-6134-4902
                Article
                cancers-13-00935
                10.3390/cancers13050935
                7956367
                33668097
                d1b75cc4-158a-44b9-827f-f160a7821adc
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 29 January 2021
                : 19 February 2021
                Categories
                Review

                collagen,col11a1,biomarker,cancer-associated fibroblasts,metastasis,chemoresistance

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