Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases

Abstract

In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.

Tumor vessel co-option: The past & the future

“…Therefore, one may consider such strategies to seek blockade of motility- and adhesion-related molecules in cancer cells, or inducing a “hot” immune environment (e.g. containing immune cell populations with anti-tumor activities) in vessel co-opted tumors ( 4 , 110 , 122 ).…”

Coalescent angiogenesis—evidence for a novel concept of vascular network maturation

“…There is evidence that angiogenesis in adult lungs is generally limited, except in pathological conditions such as tumor growth, wound healing, or fibrosis. With respect to tumor growth, there is a non-angiogenic process described as vessel co-option, which is an alternative mechanism of generating the blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction in highly vascularized organs like lung, brain, and colon [51][52][53][54][55]. Here tumor cells grow into preexisting mature blood vessels independently of stimulating new blood vessel formation.…”

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives, and recent mechanistic insights

“…Haas G Front Cell Dev Biol. 2021 121 Vessel co-option and the HGPs of liver metastases but also of tumours growing in other organs are discussed. The idea of the distinct metabolic status of cancer cells in the replacement HGP being a potential therapeutic target is launched in this review.…”