Escape mechanisms after antiangiogenic treatment, or why are the tumors growing again?

Abstract

�nhi�itors of angiogenesis an� ra�iation in�uce compensatory changes in the tumor �as� �nhi�itors of angiogenesis an� ra�iation in�uce compensatory changes in the tumor �as� culature �oth �uring an� after cessation of treatment. �n numerous preclinical stu�ies, angiogenesis inhi�itors were shown to �e efficient in the treatment of many pathological con�itions, inclu�ing soli� cancers. �n most clinical trials, howe�er, this approach turne� out to ha�e no significant effect, especially if applie� as monotherapy. Reco�ery of tumors after therapy is a major pro�lem in the management of cancer patients. The mechanisms un�erlying tumor reco�ery (or therapy resistance)ha�e not yet �een explicitly eluci�ate�. This re�iew �eals with the transient switch from sprouting to intussuscepti�e angiogenesis, which may �e an a�apti�e response of tumor �asculature to cancer therapy that allows the �asculature to maintain its functional properties. Potential can�i�ates for molecular targeting of this angioa�apti�e mechanism are yet to �e eluci�ate� in or�er to impro�e the currently poor efficacy of contemporary antiangiogenic therapies. KEY WORDS: antiangiogenic therapy, anticancer therapy, protein tyrosine kinase inhibitor, tumor recovery, intussusceptive angiogenesis, escape mechanism Tumor angiogenesisAngiogenesis, the process of formation of new blood vessels from pre-existing ones, plays an essential role in the tumour growth and progression. New vascular segments are needed to supply the increasing tumour mass with oxygen and nutrients. Hence, the crucial step for tumour growth above the size of 1-2 mm 3 is the "angiogenic switch", when the tumour gains capability to produce angiogenic factors and induce angiogenesis (Hanahan and Folkman, 1996). Modes of angiogenesisTwo major modes of angio ge nesis have been described, namely sprouting and intussusception (often also called "non-sprouting" or splitting) (Burri et al., 2004). Sprouting angiogenesis was described more than 150 years ago and has been in the focus of research groups for many decades. This mode of angiogenesis occurs by outgrowth of abluminal sprouts which subsequently merge with existing capillaries. Degradation of endothelial basement membranes (obviously associated with increased vessel permeability) as well as proliferation of endothelial cells are essential for this process (van Hinsbergh and Koolwijk, 2008). This mode of angiogenesis Int.

Inhibition of the placental growth factor decreases burden of cholangiocarcinoma and hepatocellular carcinoma in a transgenic mouse model

“…Several studies have shown that targeting the VEGF pathway often induces 'angiogenic escape' by upregulating other angiogenic factors [34,35]. Therefore, we have measured expression levels of VEGF, as angiogenic escape of PlGF treatment is likely to act through this factor [15].…”

Intussusceptive Angiogenesis: A Biologically Relevant Form of Angiogenesis

“…In contrast, IA, also called splitting angiogenesis or nonsprouting angiogenesis, was discovered in the late eighties of the 20th century and remains poorly investigated [10,11,41]. Nevertheless, IA seems to play a major role in the growth and remodeling of most vascular beds, including the vascular beds of tumors [12,42,43]. …”

“…Furthermore, recent evidence suggests that tumors respond with an angiogenic switch from SA to IA following ionizing radiation or antiangiogenic drug therapy using PTK787/ZK222584, a broad range tyrosine kinase inhibitor. These treatments are mainly designed to stop SA but lose their effect because the process of IA enables the vascular network to keep growing [12,43,60]. Consequently, future therapies will need to target both mechanisms of angiogenesis in order to be effective.…”

Vascular normalization window: A positive prognostic foresight for head and neck cancer

“…These agents when used in combination with radiation or other chemotherapeutic agents or both, enhances the tumor response to radiation and increases the overall survival rate of patients. When an antiangiogenic agent is applied alone, cancer cells might switch from angiogenic sprouting to intussuscepted mode [41] which eventually promotes a second wave of angiogenesis. [42] This angiogenic switch of the tumor vasculature makes it more resistant to antiangiogenic agents or radiation therapy since the vessels become mature, rigid, and less vulnerable to VEGF inhibition.…”