Endoglin Targeting in Colorectal Tumor Microenvironment

In this issue of Clinical Cancer Research, Paauwe and colleagues evaluated the functional impact of endoglin signaling in cancer-associated fibroblasts (CAF) in colorectal cancer (1). Endoglin-expressing (endoglin⁺) CAFs promote the metastasis of colorectal cancer cells, and targeting them using the endoglin-neutralizing antibody TRC105 controlled metastatic disease in mice. This study brings into focus the potential benefit of targeting multiple protumorigenic cell types in the colorectal tumor microenvironment (TME).

Clinical responses to therapies that target the TME have energized efforts to better decipher the functional complexity of the TME in cancer progression and metastasis. In contrast to cancer cell–centered therapeutic approaches, targeting cancer-supporting microenvironments may also draw its advantage(s) by being less likely to encounter drug resistance due to the genetic stability of the targets. The critical and diverse functions of the distinct cell types in the TME have been increasingly recognized. This, in part, has enabled the development of novel therapeutic approaches to enhance antitumor responses and/or limit protumor actions of the TME. The prowess of immunotherapy, where immune cells are modulated to increase their antitumor activity or decrease their immunosuppressive functions, redefined the long-standing clinical limitations associated with specific cancer types, and offered support in favor of TME targeting to significantly impact cancer progression and metastatic spread.

Metastatic disease is nearly ubiquitous for patients with late-stage colorectal cancer, and a better understanding of the cancer-promoting functions of the colorectal TME may enable a better control of the lethal disease. A dominant cell population in the TME of colorectal cancer is mesenchymal-like cells, generally referred to as CAFs, which may emerge from a subverted host's response to promote tumor growth, and present a potentially attractive therapeutic target (1). However, targeting CAFs is a challenging task due their heterogeneity and double-edged role in cancer progression, with both tumor-promoting and tumor-restraining functions (2). The lack of defining markers or pathways to univocally identify CAFs as tumor-promoting and effectively targeting them further defies the development of meaningful, novel CAF-targeting therapeutics.

In this recent study, Paauwe and colleagues identified endoglin expression in CAFs in a cohort of patients with colorectal cancer (Fig. 1). Endoglin (ENG, CD105), a TGFβ/BMP-9 coreceptor expressed on proliferating endothelial cells, plays a critical role in tumor angiogenesis. The endoglin-neutralizing antibody, TRC105 (carotuximab, TRACON Pharmaceuticals), which effectively inhibits BMP-9–mediated signaling on endothelial cells, has entered clinical testing for angiosarcoma and various carcinomas. Although endoglin expression in CAFs was reported previously (3), its role in the progression of colorectal cancer remained unknown. Endoglin⁺ CAFs were not only predominantly found at the invasive borders of the colorectal cancer tumors, they were also detected in metastases in lymph nodes and liver (1). CAF-specific endoglin expression increased with tumor stage and correlated with worse metastasis-free survival for patients with stage II colorectal cancer (1). Using primary cultures of colorectal cancer patient–derived CAFs, the authors demonstrated that the association between endoglin expression in CAFs and their invasive potential was mediated, at least in part, by BMP-9 signaling, and that treatment of CAFs with TRC105 limited their invasive phenotype (1). The impact of endoglin⁺ CAFs targeting was further ascertained in two distinct preclinical systems. In a zebrafish model, mouse embryonic fibroblasts were shown to promote, in an endoglin-dependent manner, the ability of mouse colorectal cancer cells to form liver metastases. In a mouse model of colorectal cancer metastasis, in which CAFs and HT29 colorectal cancer cells were coinjected, endoglin targeting using TRC105 significantly reduced liver metastases. In the latter, CAFs were pretreated with TRC105 and treatment continued until endpoint, supporting that TRC105 treatment inhibited the CAF-facilitated formation of metastases.

The study of Paauwe and colleagues identified endoglin⁺ colorectal CAFs as a potential therapeutic target for TRC105 therapy (Fig. 1). Their results indicated that endoglin targeting, using TRC105, effectively suppressed the CAF-facilitated metastasis of colorectal cancer cells. Their work contributes to the exciting development of “TME network therapeutics,” wherein drugs with multiple functions or targets in the TME could offer added benefits in specific cancer types, and could synergistically improve other cancer therapies. Critically, the authors showed a correlation between endoglin⁺ CAFs and poor outcome in stage II, but not in stage III colorectal cancer. Their subsequent experiments underscore that this association is functionally linked to the prometastatic functions of endoglin-mediated signaling in a subset (endoglin⁺) of colorectal cancer CAFs. Although the impact of targeting endoglin on tumor endothelial cells has been well-characterized (4), further studies will inform on the impact of such targeting on other components of the TME, such as macrophages (5). The tumor-promoting function of endoglin⁺ CAFs was also reported in the context prostate cancer (3), and the sum impact of endoglin targeting in distinct cancer types, at various stages of disease progression, requires further study. From their study, Paauwe and colleagues suggest that endoglin signaling in CAFs may be implicated in extracellular matrix interactions and remodeling. This intriguing possibility is aligned with the studies supporting that CAFs can migrate to a secondary organ and build tracks for cancer-cell migration (6).

V.S. LeBleu is a consultant for Codiak Biosciences. No potential conflicts of interest were disclosed by the other author.

Conception and design: V.S. LeBleu

Writing, review, and/or revision of the manuscript: L.M. Becker

V.S. LeBleu is supported by the University of Texas MD Anderson Khalifa Bin Zayed Al Nahyan Foundation.