Is risk of axillary lymph node metastasis associated with proximity of breast cancer to the skin?

The radiosensitization effect of gold nanoparticles (GNPs) has been demonstrated both in vitro and in vivo in radiation therapy. The purpose of this study was to systematically assess the biological effectiveness of GNPs distributed in the extracellular media for realistic cell geometries. TOPAS-nBio simulations were used to determine the nanometre-scale radial dose distributions around the GNPs, which were subsequently used to predict the radiation dose response of cells surrounded by GNPs. MDA-MB-231 human breast cancer cells and F-98 rat glioma cells were used as models to assess different cell geometries by changing 1) the cell shape, 2) the nucleus location within the cell, 3) the size of GNPs, and 4) the photon energy. The results show that the sensitivity enhancement ratio (SER) was increased up to a factor of 1.2 when the location of the nucleus is close to the cell membrane for elliptical-shaped cells. Heat-maps of damage-likelihoods show that most of the lethal events occur in the regions of the nuclei closest to the membrane, potentially causing highly clustered damage patterns. The effect of the GNP size on radiosensitization was limited when the GNPs were located outside the cell. The improved modelling of the cell geometry was shown to be crucial because the dose enhancement caused by GNPs falls off rapidly with distance from the GNPs. We conclude that radiosensitization can be achieved for kV photons even without cellular uptake of GNPs when the nucleus is shifted towards the cell membrane. Furthermore, damage was found to concentrate in a small region of the nucleus in close proximity to the extracellular, GNP-laden region.

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“…1(a)). 27, 28 For kV photons, the percent depth doses and energy spectra at 2, 5, and 10 cm depth are shown in fig. 2.…”

Section: Methodsmentioning

confidence: 99%

Dependence of gold nanoparticle radiosensitization on cell geometry

Sung

McNamara

et al. 2017

Nanoscale

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“…Our results also indicate that human tumors formed near epithelial surfaces may have access, chiefly, to small lymphatics, rather than sparser, nonsprouting, collecting lymphatics to which more deeply-located tumors predominantly have access. Hence human tumors that may originate close to skin, such as breast carcinomas [21], would have a greater propensity to spread lymphogenously. Whilst VEGF-C or VEGF-D expression has been suggested as a prognostic indicator in several cancer types [7,8,14,15], longstanding clinicopathological knowledge and more recent evidence that traditional indicators (such as the site of the tumor or tumor thickness and vertical growth phase in melanoma) remain key predictors of metastasis and determinants of clinical staging and prognosis [1,21,47,48], should not be neglected.…”

Section: Discussionmentioning

confidence: 99%

“…Hence human tumors that may originate close to skin, such as breast carcinomas [21], would have a greater propensity to spread lymphogenously. Whilst VEGF-C or VEGF-D expression has been suggested as a prognostic indicator in several cancer types [7,8,14,15], longstanding clinicopathological knowledge and more recent evidence that traditional indicators (such as the site of the tumor or tumor thickness and vertical growth phase in melanoma) remain key predictors of metastasis and determinants of clinical staging and prognosis [1,21,47,48], should not be neglected. One of the limitations of this study is that other cell types in the tumor microenvironment that may additionally influence lymphangiogenesis have not been studied.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the size and location of a tumor, and depth of tumor invasion remain key indicators in the pathological assessment of many types of cancer. For example, the depth of an invading melanoma "cell front" is a key prognostic determinant; and more recently, it was observed that invasive breast cancers involving or near overlying skin have higher metastasis rates Page 6 and worse prognoses than size-matched tumors located more deeply [21]. Further, the deepest tumor fronts in colorectal cancer express higher VEGF-C or VEGF-D levels than more superficial tumor tissue, and expression of these growth factors is independently related to poor prognosis [22].…”

Section: Introductionmentioning

confidence: 99%

“…This suggests that, in addition to requisite lymphangiogenic growth factors, other features such as the anatomical tumor location remain important determinants of LN spread [21].…”

Section: Introductionmentioning

confidence: 99%

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Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis

Shayan

Inder

Karnezis

et al. 2012

Clin Exp Metastasis

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Tumor metastasis to lymph nodes is a key indicator of patient survival, and is enhanced by the neo-lymphatics induced by tumor-secreted VEGF-C or VEGF-D, acting via VEGFR-3 signalling. These targets constitute important avenues for anti-metastatic treatment. Despite this new understanding, clinical observations linking metastasis with tumor depth or location suggest that lymphangiogenic growth factors are not the sole determinants of metastasis. Here we explored the influence of tumor proximity to lymphatics capable of responding to growth factors on nodal metastasis in a murine VEGF-D over-expression tumor model. We found that primary tumor location profoundly influenced VEGF-D-mediated lymph node metastasis: 89 % of tumors associated with the flank skin metastasised, in contrast with only 19 % of tumors located more deeply on the body wall (p< 0.01). Lymphatics in metastatic tumors arose from small lymphatics, and displayed distinct molecular and morphological profiles compared with those found in normal lymphatics. Smaller lymphatic subtypes were more abundant in skin (2.5-fold, p < 0.01) than in body wall, providing a richer source of lymphatics for VEGF-D(+) skin tumors, a phenomenon also confirmed in human samples. This study shows that the proximity of a VEGF-D(+) primary tumor to small lymphatics is an important determinant of metastasis. These observations may explain why tumor location relative to the lymphatic network is prognostically important for some human cancers.

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Monte Carlo simulations shed light on Bathsheba's suspect breast

Heijblom

Meijer

Leeuwen

et al. 2012

Journal of Biophotonics

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In 1654, Rembrandt van Rijn painted his famous painting Bathsheba at her Bath. Over the years, the depiction of Bathsheba's left breast and especially the presence of local discoloration, has generated debate on whether Rembrandt's Bathsheba suffered from breast cancer. Historical, medical and artistic arguments appeared to be not sufficient to prove if Bathsheba's model truly suffered from breast cancer. However, the bluish discoloration of the breast is an intriguing aspect from a biomedical optics point of view that might help us ending the old debate. By using Monte Carlo simulations in combination with the retinex theory of color vision, we showed that is highly unlikely that breast cancer results in a local bluish discoloration of the skin as is present on Bathsheba's breast.

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Is risk of axillary lymph node metastasis associated with proximity of breast cancer to the skin?

Cited by 19 publications

References 15 publications

Dependence of gold nanoparticle radiosensitization on cell geometry

Dependence of gold nanoparticle radiosensitization on cell geometry

Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis

Monte Carlo simulations shed light on Bathsheba's suspect breast

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