Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • br Emerging Vascular Mechanisms of AA Therapy Resistance Exp

    2023-05-17


    Emerging Vascular Mechanisms of AA Therapy Resistance Experimental and clinical evidence indicates that physiological angiogenesis generates blood vessels capable of restoring perfusion [1], whereas tumoral angiogenesis gives rise to vessels that are structurally and functionally abnormal, therein disrupting perfusion [10]. This stark contrast bears significant clinical relevance, since perfusion not only affects the degree of IH, but also determines the fraction of CCs potentially available for eradication by intravenous or orally available anticancer drugs, thus influencing therapy resistance (Figure 1). Recent preclinical and clinical data suggest that AA therapies transiently repair the abnormal tumor vasculature, thereby improving O2 and drug delivery whilst decreasing interstitial fluid pressure [11]. This process, known as ‘vessel normalization’, occurs within a narrow temporal window and is dose dependent [12]. However, preclinical and clinical data have thus far failed to provide definitive evidence of whether vessel normalization is a common mechanism explaining how an AA drug improves the efficacy of chemotherapy. Indeed, in patients with non-small cell lung carcinoma, the anti-VEGF neutralizing antibody bevacizumab decreased tumor perfusion and [11C]docetaxel uptake, an effect that persisted for 4 days after starting treatment [13]. A similar result was observed in patients with renal cell carcinoma (RCC), in whom vessel normalization was not accompanied by enhanced tumor delivery of radiolabeled 89Zr-bevacizumab [14]. In addition, preclinical studies have shown that bevacizumab administration hampers intratumor delivery and/or accumulation of netarsudil synthesis targeting VEGF, VEGFR2, EGFR, and IGFR1, as well as tracers utilized for the detection of IH [15–17]. Bevacizumab or DC101 (an anti-VEGFR2 antibody) increased IH whilst decreasing vascularization and perfusion in colorectal (CRC) and breast cancer mouse models [16,18]. Integration of these data suggests that vessel normalization does not always improve the delivery of chemotherapeutic drugs and/or tumor oxygenation; moreover, the precise delineation and exploitation of a therapeutic vessel normalization window in patients with cancer becomes difficult within the context of metastatic tumor masses growing asynchronically in multiple organ sites. An exceptional clinical setting wherein a single normalization window can be defined is the case of primary tumors of the central nervous system that seldom progress to metastatic disease. Recent studies showed that resistance to AA therapy can be mediated by two nonangiogenic processes, known as ‘vessel co-option’ and ‘vasculogenic mimicry’ (VM). In vessel co-option, invading CCs hijack existing vessels in highly vascularized organs, such as the lung, liver, brain, and lymph nodes, which require little or no angiogenesis (reviewed in [19]). Consistently, vessel co-option is associated with acquired resistance to bevacizumab in patients bearing hepatic metastases from CRCs [20] and to sorafenib, in some instances of primary hepatocellular carcinoma (HCC) [21,22]. Bridgeman et al. showed that vessel co-option can also mediate innate resistance to sunitinib in lung metastasis models [23]. It will be crucial to determine whether co-opted vessels are endowed with structural and functional abnormalities worsening IH, perfusion, and drug delivery while enhancing HIF-α signaling. VM is defined as the de novo formation of perfusable vascular-like networks by CCs expressing endothelial and stem cell markers that contribute to the progression of astrocytomas, carcinomas, glioblastomas, melanomas, and sarcomas [24]. Interestingly, Li et al. showed that cells engaged in VM rely on HIF-α-dependent VE-cadherin and VEGFR2 expression [25], whereas Kuczynski et al. demonstrated that vessel co-option is associated with the induction of the epithelial-to-mesenchymal transition (EMT) that facilitates HCC cell invasion into the liver parenchyma after sorafenib treatment [21]. These results open the possibility that HIF-α signaling contributes to acquired and innate AA therapy resistance through modulation of EMT during vessel co-option and VM.