Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases

Jeong, Han‐Sin; Jones, Dennis; Liao, Shan; Wattson, Daniel A.; Cui, Cheryl H.; Duda, Dan G.; Willett, Christopher G.; Jain, Rakesh K.; Padera, Timothy P.

doi:10.1093/jnci/djv155

Cited by 108 publications

(133 citation statements)

References 51 publications

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“…As metastatic lesions grow, the surface area of the blood vessels becomes limiting, causing the distribution of cancer cells to revert to that of a random distribution. This phenotype is consistent with the lack of sprouting angiogenesis in lymph node metastases (25). In lymph nodes with large lesions, 1%±0.5% of cancer cells were found in blood vessels (Fig.…”

supporting

confidence: 86%

Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice

Pereira

Kedrin

Seano

et al. 2018

Science

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380

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Lymph node metastases in cancer patients are associated with tumor aggressiveness, poorer prognosis and the recommendation for systemic therapy. Whether cancer cells in lymph nodes can seed distant metastases has been a subject of considerable debate. We studied mice implanted with cancer cells (mammary carcinoma, squamous cell carcinoma or melanoma) expressing the photoconvertible protein Dendra2. This technology allowed us to selectively photoconvert metastatic cells in the lymph node and trace their fate. We found that a fraction of these cells invaded lymph node blood vessels, entered the blood circulation, and colonized the lung. Thus, in mouse models, lymph node metastases can be a source of cancer cells for distant metastases. Whether this mode of dissemination occurs in human cancer remains to be determined.

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supporting

confidence: 86%

Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice

Pereira

Kedrin

Seano

et al. 2018

Science

Self Cite

380

311

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“…3, bottom right). In this context, our results also offer a potential explanation for the failure of antiangiogenesis therapy postoperatively (2), because micrometastatic lesions might have very low MVD and lack angiogenesis (28). Additionally, a significant fraction of BCs are desmoplastic (29,30), which might cause vessel compression and reduce the patency of vessels (31)(32)(33).…”

Section: Low Vascularity Poorly Perfusedmentioning

confidence: 80%

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

Tolaney

Boucher

Duda

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.antiangiogenic therapy | circulating and tissue biomarkers | PAM50 gene signature | cellular proliferation

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“…By contrast, they were mainly characterized by bulky nodal disease, pointing towards tumors with a predisposition to lymphatic spread, and a relative inability for hematogenous spread. Lymphatic spread is unique, as neovascularization is not an essential prerequisite (11). It was recently demonstrated that, compared with hematogenous spread, lymphatic spread is independent of epithelial-to-mesenchymal transition (EMT) in the primary tumor (12).…”

Section: Discussionmentioning

confidence: 99%

Long-term disease stabilization following treatment with erlotinib in heavily pretreated patients with wild-type epidermal growth factor receptor non-small-cell lung carcinoma: Two case reports

Sakellakis

Koutras

Pittaka

et al. 2016

Molecular and Clinical Oncology

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Abstract. Lung adenocarcinomas carrying epidermal growth factor receptor (EGFR) mutations have been identified as a unique group of entities that depend on EGFR for their proliferation and metastasis. The introduction of reversible EGFR tyrosine kinase inhibitors, such as erlotinib, has significantly affected the management of metastatic disease in this subset of patients. Interestingly, although erlotinib is highly effective in patients with EGFR mutations, it may occasionally prove useful, even in the absence of mutations. We herein present the course of two heavily pretreated patients who achieved remarkable disease stabilization over several years, despite harbouring no EGFR mutations. Our cases underscore the fact that further research is required to identify which subset of patients will benefit the most from this treatment, as a substantial minority may present with favourable outcomes.

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Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases

Cited by 108 publications

References 51 publications

Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice

Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

Long-term disease stabilization following treatment with erlotinib in heavily pretreated patients with wild-type epidermal growth factor receptor non-small-cell lung carcinoma: Two case reports

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