Editorial
The term angiogenesis was coined in 1787 [1] and the role of vessels
in cancer has being studied since. In 1971 Folkman [2] introduced the
hypothesis, until now widely accepted, that tumour growth is angiogenesis
dependent [3,4]. However, the discovery that tumours can also grow
without angiogenesis, by co-opting pre existing vessels in humans [5-8]
and in mice [9], has demonstrated that this is not always the case. This
observation provides a new aspect of the interaction between vessels and
tumours, sheds new light on the biology of the latter and has implications
for resistance to antiangiogenic drugs and development of new vascular
targeting strategies. Eventually the relationship between cancer and blood
vessels is emerging as much more complex than until recently thought.
However, as the scientific community has been investigating
the relationship between blood vessels and cancer for more than a
century, it is surprising that such complexity has been so far overlook.
However, as matter of fact, it has not overlooked but merely
discovered and then forgotten.
The research line of Folkman [4] has sprouted from the work of Ide
[10] as in 1939 he described that tumour implants in the ears of rabbits
were accompanied by formation of new capillaries leading him to the
idea that angiogenesis is necessary to support tumours. In 1971 Folkman
published a seminal paper [2] in which the idea that “the growth of solid
neoplasm is always accompanied by neovascularization” was put forward.
This hypothesis relied mostly on “in vitro” and animal models [3] with
experiments conducted in avascular sites, such as the cornea of a rabbits
[11], regarded as classic proof of concept. Subsequent work on mice has not
only confirmed the need for angiogenesis but also shown that its induction
is an early event [12]. Immunohistochemical studies of human “in situ “
breast [13] and cervical [14] carcinomas have demonstrated the enhanced
presence of micro vessels in the underlying basal membranes at this early
stage inferring that angiogenesis may represent an intermediate phase
between in situ and infiltrating carcinomas [12]. A formal classification
of intratumour vessels in human tumours maintained that they were all
newly formed [15]. The direct correlation between microvessel density
and outcome [16] further strengthened the idea of a link between
angiogenesis and tumour growth although such an association has been
subsequently strongly questioned [17]. Recently it has been concluded
that induction of angiogenesis is a hallmark of cancer as it is necessary to
addresses the needs of tumour cells for oxygen, nutrients and clearance of
catabolic products [18].
However many other investigators addressed the issue of cancer and
blood vessels in the past and many observations have been published in
the past which contrast with the angiogenesis only hypothesis. Reading
backward the literature proved to be a very enlightening experience!
In 1988 Kolin et al. [19] described some primary lung carcinomas
“often growing mainly in air spaces and preserving the pulmonary
framework as their stroma”. In 1962 Ritchie [20] writes, in the General
Pathology textbook edited by Florey that “One of the principal functions
of the stroma is to provide a blood supply within the tumour mass”. But
“sometime a tumour will supplement or replace the stroma by making use
of pre-existing structures. For example occasional tumours in the lung
grow round the alveoli using the alveolar walls in place of stroma”.
Further evidences in support of this statement were provided by
Wills in 1934 [21] in his classic book “The spread of tumours in human
body”. Here he writes that “Intra alveolar growth of tumours in the lung
is a characteristics and frequent mode of extension” in which “the plugs
of growth occupying the air sacs are themselves avascular, the septal
walls constituting the only stroma of the tumours”. Alongside providing
iconography (Figure 1A) he also quotes several papers, the oldest one
from 1861. In this study, entitled “Zwei falle von carcinosis acuta miliaris”
(Two cases of acute miliary carcinomatosis), Erichsen [22] described
how in patients with tumours in the lung the neoplastic cells occupy the
alveolar spaces but no new vessels can be seen and he illustrate his point
with a remarkable “Camera Lucida” drawing (Figure 1B).
In conclusion the blood supply of a tumour can be provided not only
by neovascularization, but also by the ability of tumours to co-opt the
pre existing host vasculature growing into non-angiogenic primary and
metastatic tumours. Alongside pure non-angiogenic tumours, a mixed
pattern of pre existing and newly formed vessels is also commonly seen.
Therefore, contrary to the theory of Folkman [3], still regarded as one of
Hallmark of Cancer [18], it is now well established that some tumours can
grow and metastatize in absence of angiogenesis [6].
The biological implications are that the triggering of hypoxia related
pathways does not necessarily lead to angiogenesis, and that to target
tumour blood supply directly may fail because of co-option. Following
the initial modest results obtained so far with anti angiogenic drugs
[23], understanding the mechanisms driving this behaviour is likely to
generate new therapy approaches for these resistant tumours. The reason
for the delay in reaching this more global view of the role of blood vessels
in cancer can be found in a communication gap between bedside and
benchtop research [24] which caused two different lines of work, mostly
on animal and “in vitro” models on one side and on histopathology on the
other, to keep going for years ignoring each other. Eventually, when one
line has become predominant, the other has been forgotten for long time
only to be re-discovered when the limitations of a partial approach to the
problem emerge.
Figure 1: A) A the microphotograph of “intra alveolar” tumours by Wills.
The original legend [21] reads: “Case 133 of osteosarcoma. Sections
of a pulmonary metastasis show alveoli occupied by plugs of growth
resembling osteoid tissue. Note the strands of growth connecting the
alveolar plugs through the septal pores (×100).
B) The original camera lucida drawing from Erichson paper [22].
The legend the author provides reads: “Cross section through a node
carcinoma of the lungs: the alveoli are shaped by with cancerous
masses confined between the elastic fibers of the lung tissue, 300 times
magnification”.
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Article Information
Article Type: Editorial
Citation: Pezzella F, Gatter K (2015) “Inducing
Angiogenesis” A Hallmark too Far. Clin Res Open Access 1(1): doi http://dx.doi.org/10.16966/2469-6714.e101
Copyright: ©2015 Pezzella F. This is an
open-access article distributed under the terms
of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Publication history:
Received date: 26 May, 2015
Accepted date: 28
May, 2015
Published date: 01 June, 2015
