**11. Mechanisms of resistance to anti-VEGF therapy**

As is the case with most cancer therapeutics, drug resistance is considered to be a major factor that limits the efficacy of anti-angiogenic agents. Two 'modes' of resistance to anti-angiogenic therapy are currently recognised: intrinsic resistance, whereby the tumour fails to respond to the therapy from the outset, and acquired resistance, whereby the tumour develops means to evade the therapy after a period of response [21, 29, 118]. It is important to realise that resistance to anti-angiogenic therapy may be attributable to either the tumour cells themselves or due to interactions with their microenvironment. In terms of specific mechanisms mediating resistance to anti-angiogenic therapy, several have been proposed.

#### **11.1 Vessel heterogeneity**

Pre-clinical work has demonstrated that although anti-angiogenic agents thwart the growth of newly established tumour vessels, they are less effective against more mature blood vessels, indicating that they may be less dependent on VEGF (**Figure 4A**) [29]. This may be due to PDGF secretion mediating pericyte recruitment, allowing young vessels to mature and survive [119]. Co-inhibition of VEGF and PDGF has been shown to generate significant anti-angiogenic and anti-tumour effects than with VEGF inhibition alone [120].

#### **11.2 Alternative pro-angiogenic signalling pathways**

Alternative pro-angiogenic signalling pathways may allow tumour vascularisation to proceed when VEGF signalling is blocked (**Figure 4B**) [29]. A large body of preclinical work has identified candidate pathways that may provide such an alternative pro-angiogenic stimulus. These include fibroblast growth factors 1 and 2 (FGF1 and FGF2) [121], hepatocyte growth factor (HGF) [122] and epidermal growth factor (EGF) [123]. Most of the above preclinical work suggests that, by inhibiting both VEGF signalling and the candidate pathway, improvements in the anti-tumour efficacy can be seen. Therefore, targeting multiple pro-angiogenic pathways may prove more beneficial than employing agents that inhibit VEGF signalling alone.

**57**

**Figure 4.**

*DOI: http://dx.doi.org/10.5772/intechopen.89667*

*Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

*Proposed mechanisms of resistance to anti-angiogenic therapy. (A–F) The potential mechanisms that tumours can utilise to evade anti-angiogenic therapy. (A) Vessel heterogeneity. Tumours can contain vessels that are at different stages of maturation making some more sensitive to therapy than others. For example, here the top vessel is immature and is abolished by therapy (grey), whilst the bottom one is mature and remains viable (red). (B) Alternative proangiogenic signalling pathway scan affect the susceptibility of vessels to therapy. Here, tumour cells (blue) have up-regulated an alternative pro-angiogenic growth factor to facilitate persistent blood vessel growth and survival despite VEGF blockade. (C) Stromal cells infiltrating into of the tumour, such as myeloid progenitors (black) or fibroblasts (green), can also mediate resistance by releasing pro-angiogenic growth factors or by physically incorporating into vessels. (D) Tumour cell adaptation to stress. Subpopulations of cancer cells in the tumour (blue) can survive the hypoxic conditions and nutrient shortage resulting from vascular destruction by employing different adaptation mechanisms. (E) Alternative tumour vascularisation mechanisms. Apart from sprouting angiogenesis, tumours may utilise alternative mechanisms to recruit a vascular supply. In intussusceptive microvascular growth, new vessels are generated by the fission of preexisting vessels. Glomeruloid angiogenesis is where tight nests of vessels, resembling the renal glomerulus, are formed. Vasculogenic mimicry is a process whereby tumour cells can create vascular-like structures themselves (blue) which are perfused as they become continuous with the host vasculature (red). In looping angiogenesis, contractile myofibroblasts (green) pull host vessels (red) out of the surrounding parenchymal tissue (pink region). Vessel co-option is a process whereby invading tumour cells engulf pre-existing vessels (red) in the normal parenchyma (pink region). (F) Selection of aggressive cells. Therapy alters the biology of the tumour* 

*cells in that they become more invasive and/or facilitate accelerated growth of metastases.*

*DOI: http://dx.doi.org/10.5772/intechopen.89667 Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

#### **Figure 4.**

*Current Cancer Treatment*

increased survival.

proposed.

**11.1 Vessel heterogeneity**

effects than with VEGF inhibition alone [120].

**11.2 Alternative pro-angiogenic signalling pathways**

3- and 5-year overall survival.

**11. Mechanisms of resistance to anti-VEGF therapy**

Tumour response was scored according to five tumour regression grades (TRG1-5) based on the proportion of fibrosis to viable tumour cells. Later, this TRG scoring system was modified for its application in CRLMs receiving different chemotherapy backbones prior to liver resection (**Figure 3A–E**) [116]. Correlation analyses have demonstrated a significant association of major histological responders with

Similar retrospective studies using the TRG in CRLMs were undertaken to see whether adding bevacizumab to chemotherapy would further increase pathological response rate, without necessarily increasing radiographic response rate, after liver resection. Indeed, several retrospective analyses demonstrated that a significantly increased percentage of patients treated with bevacizumab achieved a major pathological response and a significantly higher percentage area of tumour necrosis compared to chemotherapy-only treated patients [117]. Furthermore, the extent of pathological response correlated significantly with long-term-outcomes such as

As is the case with most cancer therapeutics, drug resistance is considered to be a major factor that limits the efficacy of anti-angiogenic agents. Two 'modes' of resistance to anti-angiogenic therapy are currently recognised: intrinsic resistance, whereby the tumour fails to respond to the therapy from the outset, and acquired resistance, whereby the tumour develops means to evade the therapy after a period of response [21, 29, 118]. It is important to realise that resistance to anti-angiogenic therapy may be attributable to either the tumour cells themselves or due to interactions with their microenvironment. In terms of specific mechanisms mediating resistance to anti-angiogenic therapy, several have been

Pre-clinical work has demonstrated that although anti-angiogenic agents thwart

Alternative pro-angiogenic signalling pathways may allow tumour vascularisation to proceed when VEGF signalling is blocked (**Figure 4B**) [29]. A large body of preclinical work has identified candidate pathways that may provide such an alternative pro-angiogenic stimulus. These include fibroblast growth factors 1 and 2 (FGF1 and FGF2) [121], hepatocyte growth factor (HGF) [122] and epidermal growth factor (EGF) [123]. Most of the above preclinical work suggests that, by inhibiting both VEGF signalling and the candidate pathway, improvements in the anti-tumour efficacy can be seen. Therefore, targeting multiple pro-angiogenic pathways may prove more beneficial than employing agents that inhibit VEGF

the growth of newly established tumour vessels, they are less effective against more mature blood vessels, indicating that they may be less dependent on VEGF (**Figure 4A**) [29]. This may be due to PDGF secretion mediating pericyte recruitment, allowing young vessels to mature and survive [119]. Co-inhibition of VEGF and PDGF has been shown to generate significant anti-angiogenic and anti-tumour

**56**

signalling alone.

*Proposed mechanisms of resistance to anti-angiogenic therapy. (A–F) The potential mechanisms that tumours can utilise to evade anti-angiogenic therapy. (A) Vessel heterogeneity. Tumours can contain vessels that are at different stages of maturation making some more sensitive to therapy than others. For example, here the top vessel is immature and is abolished by therapy (grey), whilst the bottom one is mature and remains viable (red). (B) Alternative proangiogenic signalling pathway scan affect the susceptibility of vessels to therapy. Here, tumour cells (blue) have up-regulated an alternative pro-angiogenic growth factor to facilitate persistent blood vessel growth and survival despite VEGF blockade. (C) Stromal cells infiltrating into of the tumour, such as myeloid progenitors (black) or fibroblasts (green), can also mediate resistance by releasing pro-angiogenic growth factors or by physically incorporating into vessels. (D) Tumour cell adaptation to stress. Subpopulations of cancer cells in the tumour (blue) can survive the hypoxic conditions and nutrient shortage resulting from vascular destruction by employing different adaptation mechanisms. (E) Alternative tumour vascularisation mechanisms. Apart from sprouting angiogenesis, tumours may utilise alternative mechanisms to recruit a vascular supply. In intussusceptive microvascular growth, new vessels are generated by the fission of preexisting vessels. Glomeruloid angiogenesis is where tight nests of vessels, resembling the renal glomerulus, are formed. Vasculogenic mimicry is a process whereby tumour cells can create vascular-like structures themselves (blue) which are perfused as they become continuous with the host vasculature (red). In looping angiogenesis, contractile myofibroblasts (green) pull host vessels (red) out of the surrounding parenchymal tissue (pink region). Vessel co-option is a process whereby invading tumour cells engulf pre-existing vessels (red) in the normal parenchyma (pink region). (F) Selection of aggressive cells. Therapy alters the biology of the tumour cells in that they become more invasive and/or facilitate accelerated growth of metastases.*
