Neoangiogenesis, the formation of new blood vessels, is a critical event in tumor growth [14]. Angiogenesis is a multistep process regulated by pro- and antiangiogenic factors. In cancer, genetic mutations, inflammatory processes, and hypoxia are able to tilt and sustain the angiogenic balance towards a pro-angiogenic form [14–16]. Angiogenesis is initiated when cells experience low oxygen tensions and develop adaptive responses mediated by the hypoxia-inducible factor-1a (HIF-1a), which activates the expression of vascular endothelial growth factor (VEGF), the key central mediator of tumor angiogenesis. Upregulation of VEGF pathways has been shown in many different tumors [14–17]. Other angiogenic activators such as placental growth factor (PlGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and matrix metalloproteinases also facilitate the tumor angiogenic process.

Tumor angiogenesis is sustained and uncontrolled and lacks remodelling, ultimately resulting in the development of a heterogeneous and disorganized network of tortuous and dilated vessels with characteristically show increased microvessel permeability. Tumor microvessel hyperpermeability to macromolecules is a direct contributor to raised hydrostatic interstitial fluid pressure which itself acts as a barrier to successful therapy [18].

Structural microvessel abnormalities also exacerbate the already precarious oxygen supply to tumors causing further tumor hypoxia [14–19]. Tumors attempt to overcome oxygen deficiency by further overexpressing pro-angiogenic factors thus creating a vicious feedback cycle of hypoxia-abnormal angiogenesis. This abnormal cycling via HIF-1a also promotes the development an aggressive tumor phenotype prone to spread via metastasis pathways [2].

Tumor angiogenesis is a proven target for anticancer therapy (ACT). In this setting, two distinct approaches for antiangiogenesis therapy (AAT) in tumors have emerged: inhibition of growth factors/signalling pathways necessary for endothelial cells growth and proliferation and therapies that directly target the established tumor vasculature. In the latter group, we can include vascular disruptive agents (VDAs) but also radiotherapy. Antiangiogenic target therapies act via the inhibition of angiogenesis often mediated by VEGF-action blockade. In the short term, they may also act through vascular normalization, which results in reduction in interstitial fluid pressure and temporary improved tumor oxygenation. VDAs selectively target endothelial cells and pericytes of the tumor vasculature [18] producing an acute vascular shutdown and tumor necrosis but have not yet been approved for clinical use [6, 7, 16–21]. Radiation-induced tumor cell death is usually attributed to DNA damage to tumor cells, thus triggering cell death by apoptosis and/or necrosis. However, radiation may also cause damage to endothelial cells. Stereotactic radiotherapy (SRT), which maximizes radiation dose/fraction, can lead to rapid endothelial apoptosis and to the obliteration of the tumor vasculature [21].

Different intracellular pathways are involved in tumor proliferation and metabolic activity regulation. The majority of human epithelial cancers are noted for upregulation of cell surface receptors capable of activation by growth factors including those of the epidermal growth factor receptor (EGFR) family, such as EGFR and HER2 [22, 23]. Given the importance of the EGFR pathway in cancer development, both anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase receptor inhibitors (TKIs) have been developed. KIT receptor also plays critical oncogenic roles in a broad spectrum of hematologic and solid tumors controlling various cellular processes such as proliferation and differentiation, apoptosis, and metabolic tumor activity [24]. Imatinib mesylate inhibits KIT kinase activity and represents the front-line drug for the treatment of unresectable and advanced gastrointestinal stromal tumors (GISTs). Beside this, a variety of human malignancies have anaplastic lymphoma kinase (ALK) translocations. In lung cancers, the presence of a fusion gene, EML4-ALK, activates ALK overexpression, which contributes to increased cell proliferation and survival signalling via a number of intracellular pathways. Lung cancer cell lines harboring ALK gene rearrangements are sensitive to ALK inhibitor crizotinib [25, 26].

Different pathways mediate downstream effects of EGFR, ALK, or KIT pathways, including the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) pathway, which activates cellular survival signals [27], and the RAS-RAF-MAPK pathway [28] that affects cell proliferation, tumor invasion, and metastasis. Downstream pathways are also viable oncologic targets. Several drugs such as everolimus or temsirolimus specifically target the downstream signalling pathway PI3K/Akt/mTOR in renal carcinoma [27]. This strategy has merit for breast cancer also [29]. Beside this, approximately 40–60 % of malignant melanomas contain a BRAF mutation. The RAS family members act as critical mediators in cellular growth and survival. BRAF inhibitors have shown notable activity in patients with melanoma with BRAF gene mutations [28].

Hormonal therapy (HT) constitutes a different type of therapy for modulating tumor proliferation. Steroid hormone growth factors interact with nuclear receptors to activate the transcription of genes whose products stimulate the growth and viability of hormone-dependent malignancies [30, 31]. HT blocks the effects of hormones in tumors, mainly in breast cancer (BC) and in prostate tumors. A number of novel hormonal therapies have recently been introduced for the treatment of metastatic breast and prostate cancers including drugs targeting the endogenous production of estrogen/testosterone and selective estrogen/androgen receptor degraders (SERDs/SARDs).

The receptor tyrosine kinase MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. Abnormal MET activation and causes por clinical outcomes. Abnormal MET activation correlates with poor prognosis in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic [32]. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity towards MET and VEGF receptor 2. It is currently being evaluated in a number of tumor types with encouraging results in prostate cancer (PC) [33, 34].

Tumor cells are able to evade immune recognition and suppress immune reactivity despite the fact that many tumors elicit a strong immune response [35]. Nevertheless, the immune system can respond to some types of tumors that display highly immunogenic cancer cell-related antigens. It is also possible to activate the immune system into an antitumor state [5]. Immunotherapy has been successfully introduced into the clinic for treatment of metastatic prostate and breast tumors, lymphoma, and melanoma.

When considering therapy effects on tumors, there appear to be differences in imaging observations between therapies [6–13, 36–41]. In each case, imaging findings appear to depend on anatomic sites and on interactions between specific tissue microstructure and the mechanism of action of therapy given. Traditional oncologic therapies, such as chemotherapy or radiotherapy, do not selectively attack malignant cells, but affect proliferating cells regardless of their malignant status. These therapies cause cellular lysis often via necrosis or apoptotic mechanisms. Tumor cell loss will lead to difference changes depending on the imaging technique applied. On DW-MRI, cellular lysis results in increased water diffusion, which increases apparent diffusion coefficient (ADC) values [36–38]. Chemotherapy and radiotherapy have also been shown to have an indirect antivascular effect via tumor cell killing and subsequent withdrawal of angiogenic cytokines; the latter is needed as a survival factor for immature vessels. On DCE imaging, a favorable tumor response to chemotherapy results in decreases in the rate and magnitude of enhancement for a number of tumor types [38, 39]. Such decreases in DCE-MRI kinetic parameters may be delayed after radiation therapy when an initial hyperemic response is often seen [42]. Concomitantly, FDG-PET shows reductions in glucose metabolism activity of tumors in response to therapy [40]. Applying this knowledge to novel biologic targeted drugs, hormonal therapy, advanced forms of radiation therapy, and interventional techniques, such as embolization or ablation, is not always straightforward. These aspects are considered more fully below.