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.

Keywords: angiogenesis; brain metastasis; colorectal cancer; histopathological growth patterns; liver metastasases; lung metastasis; vessel co-option.

Figure 1

Modes of vascularization (A–E). (A) The mechanism of sprouting angiogenesis. As the tumor grows, sprouting of new immature vessels from a mature preexisting vessel is induced. (B) Vasculogenesis, a mechanism where a completely new vessel is formed by progenitor cells. (C) Intussusceptive angiogenesis. Hereby, a pre-existing vessel is promoted to split itself into two new ones. (D) Vascular mimicry. The tumor cells form a vessel-like structure themselves. (E) Co-option of a pre-existing mature blood vessel by expanding tumor cells.

Figure 2

HGP of CRCLM (A,B). (A) Schematic illustration of a desmoplastic CRCLM. Hereby, the defining desmoplastic rim between tumor and liver tissue is clearly visible. A dense immune cell infiltration is surrounding and also invading the metastasis. Within the desmoplastic rim, the ductular reaction is illustrated. The ingrowing vessels demonstrate sprouting angiogenesis, which is characteristic for desmoplastic CRCLM. (B) Schematic illustration of replacement CRCLM. This type of metastases is characterized by tumor cells, mimicking the liver architecture, co-option of mature pre-existing vessels, and absence of an inflammatory and fibroblastic rim.

Figure 3

Hematoxylin and Eosin stained CRCLM with different HGP (A,B). Liver tissue is labeled as L, tumor tissue as T, ductular reaction of bile ducts as BD, the immune cell infiltration as I, and the desmoplastic rim as DR. (A) CRCLM with desmoplastic HGP. The CRCLM is differentiated from the surrounding liver tissue by the HGP defining desmoplastic rim. Additionally, in the desmoplastic rim the ductular reaction, composed by proliferating bile ducts, and the inflammatory infiltration are visible. (B) CRCLM with replacement HGP. The close cell–cell contact of tumor cells and hepatocytes is clearly visible, as the tumor cells invade the liver cell plates.

Figure 4

HGP in primary lung cancer (A–F). (A) Cancer cells growing in the bronchus of the lung (black arrows). (B) In the normal alveolar parenchyma, the lung alveolar spaces are filled by air and are delimited by the alveolar walls. (C) Alveolar HGP. Cancer cells fill the alveolar air space. (D) Lepidic HGP. Cancer cells spread along the alveolar walls, but preserve some air space by not filling the alveoli completely. (E) Interstitial HGP. Cancer cells grow between the alveoli, but do not enter the alveolar space. (F) Perivascular cuffing HGP. Cancer cells grow cuff-like around blood vessels. (Figure created with vectors from Servier Medical Art. https://smart.servier.com/).

Figure 5

Glioblastoma—primary tumor. Once cancer cells reach the blood vessels, two outcomes are feasible: (i) neoplastic cells produce flectopodia and fuse with pericytes through CDC42-mediated processes to produce hybrid cell types. However, when CDC42 activity is blocked, fusion is abrogated, and pericytes might gain anti-tumor activities (assuming a peripheral-derived macrophage-like phenotype). (ii) tumor cells place themselves between astrocytes and pericytes, thereby blocking their physiological interactions and changing their normal functions (Figure created with vectors from Servier Medical Art. https://smart.servier.com/).

Figure 6

Brain—metastases. In brain metastases, tumor cells can attach to the vascular basement membrane via β1-integrin. The resultant close spatial proximity to vessels allows then the metastatic cells to co-opt the pre-existing blood vessel. In the presented model, non-angiogenic metastatic cells infiltrating the brain tissue are characterized by secretion of neuroserine protease inhibitors and expression of L1CAM. Neuroserpin blocks plasminogen activator and prevents the formation of plasmin. The inhibition of plasmin release into the microenvironment prevents both the death of cancer cells by FAS ligand and the further blockade of L1CAM (Figure created with vectors from Servier Medical Art. https://smart.servier.com/).