Cancer cell dissemination and formation of metastasis occurs in several ways: (1)

lymphatic (lymphogenous) dissemination; (2) haematogenous dissemination; (3) direct

dissemination to cavities and surfaces of the human body.
Lymphatic metastasis
The most common route of cancer cell dissemination for many carcinomas is the
lymphatics. Lymph node metastasis follows the routes of lymphatic drainage. In many types of
cancer, regional lymph nodes represent barriers to further spread of cancer cells. There are
numerous interconnections between the lymphatic and vascular systems suggesting the possible
involvement of lymphatic spreading in haematogenous metastasis as well.
Haematogenous metastasis
Haematogenous spreading of cancer cells is typical for sarcomas but is also observed in
certain carcinomas such as renal cell. Cancer cells detach from the primary tumour and intravasate
into venous flow. These disseminated cells are then delivered to target organs to form metastases
(Figure 7.2). There are two hypotheses to explain the process of haematogenous metastasis:
mechanistic (blood flow) and seed and soil (organ microenvironment) originally proposed by
Paget. These hypotheses complement each other to explain how metastasis develops.
Mechanistically, the prevalence of certain metastatic sites depends on where the primary tumour
is localized in the body. For example, the liver is the first organ through which venous blood flow
from colon, gastric, and pancreatic cancer passes, so these types of cancer frequently metastasize
to the liver (Table 7.1). Metastatic breast cancer cells are delivered by venous flow to the right
heart, which delivers blood to the lungs. Metastasis to brain and bone is formed by cancer cells
delivered with arterial blood. In this case, metastatic cancer cells (from the primary tumour) pass
through the pulmonary vascular system, or lung metastatic lesions release cancer cells to seed
secondary metastasis in brain and bone as seen for breast and lung cancer.
The seed and soil hypothesis suggests that seeding and growth of cancer cells is regulated
by the biologically specific microenvironment of the target organ (soil) [16]. Indeed, it has been
demonstrated in vivo that certain kinds of cancer prefer to metastasize to specific organs regardless
of blood flow or vascular anatomy [16]. However, the seed and soil hypothesis is also compatible
with the mechanistic hypothesis of metastasis because tumour cells must reach target organs by
flow and be trapped there, at which time the soil determines whether those trapped cells will
progress to true metastases. Wood et al. [17] were the first to demonstrate the development of
haematogenous metastasis in vivo. V2 carcinoma cells (rabbit carcinoma) were injected into small
arteries in the rabbits ear, into which a chamber was inserted to observe the ear capillary network.
V2 cancer cells were rapidly trapped in the capillaries and a thrombus formed within 30 minutes
of tumour cell injection. Division of cancer cells started in 24 hours with subsequent invasion
through the endothelium (extravasation) which became obvious by 48 hours after injection. A
metastatic lesion was established 72 hours post injection. This study was the first to illustrate that
the process of haematogenous metastasis consisted of a series of sequential steps (Figure 7.2). This
was also the first study to suggest that metastasis is an inefficient process, later confirmed by Fidler
and co-workers [18] and others, since the vast majority (99.9%) of circulating cancer cells were
destroyed quickly. Since potential metastatic cells are detached from the ECM and are essentially
anchorage-independent until they seed, many of these cells likely undergo anoikis, a form of
programmed cell death, upon detachment at this stage of metastasis [19]. A variety of host factors
(e.g. blood viscosity and turbulence, platelets, T-cells, natural killer cells, and macrophages) also
contribute to the rapid death of circulating cancer cells [20]. Moreover, the passage of disseminated
tumour cells through capillaries leads to cancer cell lysis by shear forces [20]. Because only a few
cancer cells end up seeding a metastatic site, a recent hypothesis that micrometastases (defined as
metastatic tumours that are not clinically detectable) arise from cancer stem cells has been
proposed [19, 21]. This hypothesis is currently under investigation in a variety of laboratories
looking at many different tumour types. One of the challenges to studying metastasis is the lack of
good animal models that completely recapitulate the metastatic process. However, this is changing
as investigators develop new approaches that utilize genetically engineered mouse models
(GEMM) and patient-derived xenografts (which use fresh patient tumours implanted directly into
mice) to study the metastatic process [22, 23].
Direct Dissemination to Body Cavities and Surfaces
Direct dissemination of cancer cells into body cavities occurs when cancer grows through
the target organ and into a body cavity; for example, the penetration of the colonic serosal layer
by colon carcinoma leads to peritoneal dissemination. Pleural effusions and peritoneal
dissemination are the most common metastases to represent direct ways in which cancer cells
spread into a body cavity [1] , and peritoneal dissemination is a common feature of ovarian cancer.