Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

Belotti, Dorina; Pinessi, Denise; Taraboletti, Giulia

doi:10.3390/cancers13081912

Cited by 30 publications

(26 citation statements)

References 141 publications

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“…Alternative vascularization influences the poor prognosis of cancer patients, 53,54 evoking tumour resistance towards anti-angiogenic and anti-neoplastic therapy. 55 Vasculogenic mimicry is a leading pathological entity representing this state to which prompted us for a more comprehensive evaluation of VM and associated prognostic biomarkers underpinning in OSCC. In this present study, we have evaluated the correlation of VM with expression of laminin-5γ2 in predicting the survival and prognosis of OSCC.…”

Section: Discussionmentioning

confidence: 99%

Orchestrated expression of vasculogenic mimicry and laminin‐5γ2 is an independent prognostic marker in oral squamous cell carcinoma

Saha

Mitra

Alam

et al. 2022

Int J Experimental Path

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Vasculogenic mimicry (VM), an endothelial cell–independent alternative mechanism of blood supply to the malignant tumour, has long been considered as an adverse prognostic factor in many cancers. The correlation of VM with laminin‐5γ2 and the assessment of their harmonized expression as an independent risk factor have not been elucidated yet in oral squamous cell carcinoma (OSCC). CD31/PAS staining stratified 116 clinically diagnosed OSCC specimens into VM+ and VM− cohorts. The expression pattern of laminin‐5γ2 and its upstream modulator MMP2 was evaluated by immunohistochemistry and Western blot. The Kaplan–Meier and Cox regression analyses were performed to assess the survival and prognostic implications. The presence of VM demonstrated a significant correlation with the expression of laminin‐5γ2 (p < .001) and MMP2 (p < .001). This pattern was mirrored by the significant upregulation of laminin‐5γ2 and MMP2 in VM+ cohorts compared with the VM− ones. Furthermore, co‐expression of VM and laminin‐5γ2 was significantly associated with tumour grade (p = .010), primary tumour size (p < .001), lymph node metastasis (p = .001) and TNM stages (p < .001) but not with patients' age, gender, tobacco and alcohol consumption habit. Vasculogenic mimicry and laminin‐5γ2 double‐positive cohort displayed a significantly poorer disease‐free survival (DFS) and overall survival (OS). Vasculogenic mimicry, laminin‐5γ2 and their subsequent dual expression underlie a significant prognostic value for DFS [hazard ratio (HR) = 9.896, p = .028] and OS [HR = 21.401, p = .033] in OSCC patients. Together, our findings imply that VM along with laminin‐5γ2 is strongly linked to the malignant progression in OSCC and VM and laminin‐5γ2 coordination emerges as a critical prognostic biomarker for OSCC.

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Section: Discussionmentioning

confidence: 99%

Orchestrated expression of vasculogenic mimicry and laminin‐5γ2 is an independent prognostic marker in oral squamous cell carcinoma

Saha

Mitra

Alam

et al. 2022

Int J Experimental Path

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“…Clinical data show that anti-angiogenesis therapies can prolong PFS but have a limited impact on OS and do not set a permanent cure in CRC [ 142 ] . This limited clinical significance is likely due to the fact that treatment with antiangiogenic agents causes a discontinuity in the blood vessel network, which leads to a new hypoxic condition with activation of vascular mimicry, alternative pro-angiogenic pathways and recruitment of endothelial cells derived from bone marrow [ 143 ] .…”

Section: Resistance To Targeted Therapymentioning

confidence: 99%

Emerging actionable targets to treat therapy-resistant colorectal cancers

Grassilli¹,

Cerrito²

2022

CDR

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In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a “big killer” mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

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“…This mechanism is associated with higher tumor invasiveness and recurrence [60,61]. Both mechanisms mediate resistance to anti-angiogenic therapy [62,63].…”

Section: Cellular Components Of Thementioning

confidence: 99%

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

Muñoz

Girotti

Hileeto

et al. 2021

Cancers

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The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.

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Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

Cited by 30 publications

References 141 publications

Orchestrated expression of vasculogenic mimicry and laminin‐5γ2 is an independent prognostic marker in oral squamous cell carcinoma

Orchestrated expression of vasculogenic mimicry and laminin‐5γ2 is an independent prognostic marker in oral squamous cell carcinoma

Emerging actionable targets to treat therapy-resistant colorectal cancers

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

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