CANCER PATHOGENESIS

Cohnheim's theory : the theory that tumors develop from embryonic rests which do not participate in the formation of normal surrounding tissue.

Ribbert's theory : a tumor is formed from the development of cell rests owing to reduced tension in the surrounding tissues

introns harboring translocation breakpoints in tumors are significantly longer than non-translocated introns of the same genes but are not enriched significantly in sequence elements potentially involved in chromosomal rearrangements. DSB, the type of DNA damage that leads to translocations in tumors, are created at random points in the genome, and that sequence elements do not have a widespread role in the localization of these breaks^ref.

initiation : the moment of neoplastic transformation, in which only genotype is alterated (normal morphology); in toxicology, the creation of a small alteration in the genetic makeup of a cell by a low level of exposure to a carcinogen; the cell may later become neoplastic upon repeated exposure to the same carcinogen or exposure to a promoter.

• inherited susceptibility (Knudson's hypothesis^ref) : inheritance of a mutated allele (or an allele with hypermethylated CpG islands within promoter : CpG island methylator phenotype (CIMP)) of an oncosuppressor gene (2-10%) => familial cancer (family history of cancer (excluding confounding risk factors), early onset, multifocal, bilateral). E.g.
• breast carcinoma (mutations in BRCA1)
• ovary carcinoma
• familial adenomatous poliposis (FAP)
• gastric carcinoma (mutations in cadherin E)
• prostate cancers
• multiple endocrine neoplasia (MEN)
• melanoma
• neurofibromatosis / multiple neuroma / neuromatosis
• germline epigenetic silencing of MLH1 tumour suppressor leads to colorectal cancers^ref
• acquired mutation in a somatic cell => sporadic cancer. It affects more commonly epithelial cells than connective tissue cells as usually the former have a shorter cell cycle (higher proliferation rate) and hence spend proportionally more time with their DNA exposed to noxious stimuli.

Unlike rodent cells, which can be transformed with just a couple of oncogenes, human cells are notoriously difficult to transform and require several genetic lesions, including viral oncoproteins such as the SV40 large T and small T antigens, which disrupt both the p53 and RB tumour-suppressor pathways. A combination of just 4 genetic alterations (TERT, HRAS, MYC, and RAS) can transform human diploid fibroblasts leaving the p53 pathway intact : however, as only 5/16 inoculations gave rise to tumours, and the latency was relatively long - 59-98 days - another alteration might have occurred. Although these cells are normally diploid, 2 changes - on chromosomes 18 and 20 - are frequently observed^ref.
Stromal cells exposed to N-nitrosomethylurea (NMU) in vitro can transform normal mammary epithelial cells in vivo, whereas NMU-treated epithelial cells form normal ducts in vivo^ref.

promotion : the entire cell compartment of which the transformed cell is part is stimulated to proliferate (neoplastic hyperplasia) following stimulation by promoting agents, ie chronic exposure to ...

• growth factors locally produced by inflammatory cells, eg :
• chronic bronchitis in lung carcinoma
• chronic cervicitis in cervical carcinoma
• chronic pancreatitis in pancreatic carcinoma
• some hormones for hormone-dependent cancers, e.g. :
• estrogens for ER⁺ tumors
• breast adenocarcinoma
• endometrial carcinoma
• meningiomas
• progestins for progesterone receptor⁺ tumors
• androgens for AR⁺prostate adenocarcinoma
• tumors grow on average twice as fast in the daily activity phase of the circadian cycle : cancer cells show altered expression of some of their clock genes but retain organization in others. The circadian organization of clock gene expression in normal tissue and sleep activity is not disrupted by tumors.

The resulting intratumoral chronic hypoxia, particularly in conjunction with an acid microenvironment, may be directly or indirectly mutagenic. Chronic hypoxia also leads to compensatory adaptations, including tumor neoangiogenesis : neovascularization is needed for solid tumors to grow beyond a diameter of 2-3 mm.
Sources for tumor-associated endothelial cells :

• vasculogenic mimicry : the ability of aggressive tumor cells to express endothelium-associated genes and to form ECM-rich vasculogenic-like networks in 3D culture, as shown by PAS staining. The formation of these networks seems to recapitulate the embryonic development of vasculogenic networks, and are associated with the distinctly patterned, ECM-rich networks that are observed in aggressive tumours of patients with cancer. Some of these channel-like spaces were originally known as "vascular channels", because they were found to contain erythrocytes and plasma. They were thought to provide a mechanism of perfusion and a dissemination route within the tumour that functioned either independently of or simultaneously with angiogenesis (or other sources of vascularization such as vessel co-option). There is viable blood flow between tumour cell-lined vascular spaces and endothelium-lined and/or mature vasculature^ref. Even tumor cells have anticoagulant properties similar to endothelial cells and there is an exchange of blood from the normal vasculature (blood vessels) at the periphery of the tumor through tumor-cell-lined extravascular spaces within the aggressive tumor. Vasculogenic mimicry has been seen in melanoma^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10} (individuals with melanomas that have undergone vasculogenic mimicry have a poor prognosis), breast carcinoma^{ref1, ref2, ref3, ref4}, prostatic carcinoma^{ref1, ref2}, ovarian carcinoma^{ref1, ref2}, non-small cell lung carcinoma^ref, Drosophila (large tumour suppressor gene, lats-negative) tumours^ref, synoviosarcoma^ref, rhabdomyosarcoma^ref, pheochromocytoma^ref, cytotrophoblasts forming the placenta^{ref1, ref2}.
• local vessel–derived endothelial cells
• bone marrow–derived endothelial cells (BMD-ECs) involvement in tumor neovascularization has been reported to be significant^{ref1, ref2, ref3, ref4, ref5} to undetectable^{ref1, ref2, ref3} in some of the same tumor models^ref. Other studies have identified hematopoietic cells incorporated into the endothelial lining of tumor vessels^{ref1, ref2, ref3}. The reasons for these discordant findings may be the inability of some of the reported models to detect and distinguish both bone marrow– and local vessel–derived endothelial cells and the fact that most studies relied on ambigous markers to identify the endothelial-cell phenotype^ref. Other potential confounding factors may result from the genetic deficiency or transgenic models used, tumor type and organ site^{ref1, ref2}. To address these issues, BMD-ECs were quantified in perfused blood vessels in tumors using bone marrow transplantation (BMT) in 2 strains of mice and 2 tumor models: isograft and spontaneous metastasis. BMD-ECs incorporated into blood vessels with a high degree of heterogeneity between tumor types^ref, in line with emerging human data^ref. BMD-EC incorporation in vessels also varied with tumor site and with mouse strain, consistent with a recent report that documented the heterogeneity in concentration of blood circulating endothelial precursors among mouse strains^ref. The BMD-ECs may also derive from hematopoietic stem cells with "hemangioblast" activity^ref or from multipotent progenitor cells^ref. Collectively, these findings offer direct evidence for vasculogenesis during isografted tumor growth and metastasis in genetically unaltered mice. Many tumors are associated with extensive bone marrow–derived cell infiltration^{ref1, ref2, ref3, ref4, ref5} and thus, characterization of the roles of different subsets of bone marrow–derived cells in tumor development, progression, metastasis, and response to treatment may identify new therapeutic targets

Tumour-derived PDGFRb⁺ progenitor perivascular cells (PPCs) have the ability to differentiate into pericytes and regulate vessel stability and vascular survival in tumours. A subset of PDGFRb⁺ PPCs is recruited from bone marrow to perivascular sites in tumours. Specific inhibition of PDGFR signalling eliminates PDGFRb⁺ PPCs and mature pericytes around tumour vessels, leading to vascular hyperdilation and endothelial cell apoptosis in pancreatic islet tumours of transgenic Rip1Tag2 mice^ref.

Blood lakes are areas of hemorrhages generally lacking an endothelial-cell lining that are often seen in histological sections of high-grade neoplasms. The meshwork may provide a nutritional exchange for aggressive tumors that might prevent cell death within the tumor : anyway centers in the middle ot the tumor undergo necrosis, creating the cancer or intratumoral abscess, eventually infected by anaerobic bacteria (Bacteroides fragilis^ref). Compared with normal blood vessels, tumour vasculature is extremely leaky and this aids tumour progression, as plasma proteins can enter the surrounding tissue to provide a fertile environment for tumour growth. Plugging the leaks in tumour blood vessels with cavtratin (a chimeric peprtide containing the scaffolding domain of caveolin-1 - which inhibits VEGF-induced eNOS activation and reduces expression of PECAM-1 and Flt-4 / VEGFR-3- linked to a cellular internalization sequence) blocks tumour growth.
Stimulators of angiogenesis : tumor-angiogenesis factor (TAF) : a factor produced by cancer cells of solid tumors that stimulates the growth of blood vessels into the tumor.

• HUAF = FGF-1 / aFGF + FGF-2 / bFGF + ESAF
• RNPs
• TGF-a and TGF-b
• angiogenin
• Cu²⁺-heparin
• TNF-a
• thymosin-b₄ either directly or by increasing VEGF expression - and by promoting cell migration, which might be due to its actin-binding function^ref
• EPHB4 reverse signalling though ephrin B2 is involved in blood-vessel growth during development and promotes tumor angiogenesis^ref
• the enzymatic activity of COX-2 is critical for the induction of angiogenesis at least in colorectal cancers and breast cancers : PGE₂ stimulates the expression of angiogenic regulatory genes.
• HIF-1a
• loss of HIF-1a results in increased tumour progression in highly vascularized tissues where tumours can hijack preexisting normal blood vessels to grow : loss of VEGF slows growth of these tumours by impairing survival of the hijacked vasculature.
• increased HIF-1a levels are found in many human cancers and are associated with ...
• increased mortality : early stage cervical cancer^ref, radiation-treated cervical cancer^ref, LN-positive^ref or LN-negative^refbreast cancers, oligodendroglioma^ref, oropharyngeal squamous cell carcinoma (SCC) (also radiation resistance)^ref, ovarian cancer (with p53)^ref, early stage oesophageal cancer (resistance to PDT with BCL2)^ref, endometrial cancer^ref, head and neck SCCs (HIF-2a)^ref, and GIST of stomach^ref
• decreased mortality : head and neck SCCs status post-surgery^ref
• increased or decreased mortality : NSCLC^{ref1, ref2}
• effects of altered HIF-1 activity on tumour growth monitored by xenograft in nude mice :

	cell type	manipulation	rate of tumour growth	tumour angiogenesis	growth or survival of cells cultured under conditions of hypoxia or O2/glucose deprivation ex vivo
decreased HIF-1 activity	Hepa1 mouse hepatomaref1, ref2	HIF1b LOF	-	-	-
	mouse ESref	HIF-1a KO	-	-	-
	mouse ESref	HIF-1a KO	+	-	+
	MEF (T-Ag, HRASV12)ref1, ref2	HIF-1a KO	-	0	-
	HCT116, MDA-MB-435ref	HIF-1a transactivation domain (TAD)	-	-	-
	PCI-43 (pancreatic CA)ref	HIF-1a DN	-	0	-
	MEF (T-Ag, HRASV12)ref	Hif-1a KO, chemo	-	ND	-
	5 human cancer cell linesref	YC-1 i.p.	-	-	ND
increased HIF-1 activity	HCT116 (colon CA)ref	HIF-1a GOF	+	+	ND
	PCI-10 (pancreatic CA)ref	HIF-1a GOF	+	0	+
	786-O/VHLref	HIF-2a (P531A)	+	+	ND
	786-O/VHLref	HIF-1a ODD	+	ND	ND
	mouse ESref	Vhl KO	-	+	ND

The tumor cells produce FGF-2 / bFGF, VEGF, and PD-ECGF, and in turn the tumor endothelium produces PDGF, IGF-1, FGF-2 / bFGF, HB-EGF, G-CSF, and IL-6 for the cancer cells. b-defensin-29 expressed by murine tumor cells recruits bone marrow–derive DC precursors to tumors : Vegf-A expressed by the same tumor cells induces their endothelial-like specialization and migration to vessels of tumor-infiltrating DCs, which independently assemble neovasculature in vivo^ref.
Tumour xenografts and spontaneously arising tumours respond in different ways to angiogenic stress^{ref1, ref2}.
Tumor lymphangiogenesisalso may accompany tumor growth and may facilitate tumor metastasis to lymph nodes : some experiments revealed no signs of lymphangiogenesis within tumors as pressure gradients can prevent dyes injected into cancers from entering the tumoral lymphatics. Fluid pressure in tumors enlarges the lymphatics in the margin, and these hyperplastic lymphatic vessels can facilitate metastasis : even lymphatics incapable of fluid transport can serve as conduits of tumor cells. Alternatively VEGF-C and VEGF-D binding to Flt-4 / VEGFR-3 might increase metastasis by inducing lymphatic endothelial cells (LECs) to produce chemokines, which, in turn, may induce the directional migration of tumor cells into preexisting or newly formed lymphatics. Another possibility is that VEGF-C and VEGF-D might alter the adhesive capacity of LECs in a way that permits tumor cells to move into lymphatics.

Elevated interstitial fluid pressure - a hallmark of solid tumours - is commonly assumed to compress intratumour vessels. However, the interstitial fluid pressure is about equal to the microvascular pressure in tumours, making it unlikely that the collapse of permeable vessels is mediated by fluid pressure^ref : proliferating cancer cells cause intratumour vessels to compress and collapse. The delivery of therapeutic drugs to solid tumours may be impaired by structural and functional abnormalities in blood and lymphatic vessels^ref : by reducing this compressive mechanical force with diphtheria toxin (which is much less cytotoxic to mouse than to human cells^ref) rather than with taxane^ref, and opening vessels, cytotoxic cancer treatments have the potential to increase blood perfusion^ref, thereby improving drug delivery^ref. Anyway intratumoral lymphatic vessels, which are ordinarily non-functional or absent^{ref1, ref2}, do not become functional upon opening, as judged by fluorescence or ferritin microlymphangiography^ref. It is possible that tumours permanently damage lymphatic-vessel structures, such as lymphatic endothelial microvalves, or that the lack of pulsatile blood flow in tumour inhibits lymph formation. The tumour margin, in which mechanical stress is predicted to be lower, contains functional lymphatic vessels, as well as a greater fraction of open lymphatics than is found in intratumour regions. Compressive forces inhibit tumur cell growth^ref and upregulate adhesion molecules^ref. Clinically, tumours can compress large vessels and the spinal cord.
In contrast to VEGF-A, VEGF-C does not increase the growth of primary tumors, but instead induces expansion of lymphatic networks within sentinel lymph nodes, even before the onset of metastasis. Once the metastatic cells arrived at the sentinel lymph nodes, the extent of lymphangiogenesis at these sites increased. Importantly, in mice with metastasis-containing sentinel lymph nodes, tumors that expressed VEGF-C were more likely to metastasize to additional organs, such as distal lymph nodes and lungs. No metastases were observed in distant organs in the absence of lymph node metastases^ref.
Roles for endogenous cytokines in tumour pathogenesis :

• IL-1b is required for tumour invasion and angiogenesis^ref
• IL-6 is required for chemically induced lymphomas^{ref1, ref2}
• IL-12 inhibits chemical carcinogenesis^ref
• IL-15 promoter NKT cell leukaemias^ref
• IFN-g inhibits chemical carcinogenesis; inhibits lymphomas (expecially with perforin); Stat1 and Rag2 inhibit carcinomas^{ref1, ref2, ref3, ref4, ref5}
• CSF-1 / M-CSF promotes breast cancer invasion^ref
• GM-CSF inhibits lymphomas and carcinomas (with Ifn-g and Il-3)^ref
• TNF-a is required for chemically-induced skin cancers^ref
• MIF inhibits p53-tumour-suppressor functions^ref
• TGF-b inhibits colon carcinomas (with Rag2)^ref
• CD178 / FasL inhibits lymphomagenesis^ref

Activation of STATs in human cancers :

• STAT3 : chronic myelogenous leukema (CML), EBV-related Burkitt's lymphoma, CTCL, NHLs, anaplastic large cell lymphoma (ALCL), melanoma, ovarian cancer, lung cancer, pancreatic cancer, prostate cancers
• STAT5 : large granular lymphocyte leukemia (LGL)
• STAT1 and STAT3 : multiple myeloma
• STAT1 and STAT5 : erythroleukemia
• STAT3 and STAT5 : HTLV-1-dependent leukemia
• STAT1, STAT3 and STAT5 : acute myelogenous leukemia (AML), breast cancer, head and neck cancer

progression : aggressive tumour cells might revert to an undifferentiated, embryonic-like phenotype, expressing genes that are usually expressed by precursors of endothelial, epithelial, pericyte, fibroblast, haematopoietic, kidney, neuronal, muscle and several other cell types. Given tumour cell plasticity, many of the biological properties that are relevant to embryogenesis are also important for tumour growth

• early progression / preinvasive lesions (once termed "precancerous lesions") : dysplasia (abnormality of development)
• light dysplasia : nuclear dysplasia (cellular atypia : irregular or not conform to type)
• polymetrism : alteration in size
• polymorphism : alteration in shape
• increased nucleus-to-cytoplasm volume ratio
• nuclear polymorphism
• cytological polymorphism
• loss of polarity in epithelial cells
• polychromatism : alteration in staining properties
• nuclear hyperchromasia due to polyploid
• moderate dysplasia (atypical mitoses)
• severe dysplasia / carcinoma in situ (cis)
Huntingtin interacting protein-1 (HIP1) interacts with clathrin and the endocytic adaptor protein complex AP2 and is a cofactor in receptor-mediated endocytosis that is upregulated in various human epithelial cancers, conferring the ability to grow in the absence of anchorage and increased sensitivity to grow factors (upregulation of EGFR, FGFR3, and FGFR4 by decrease in receptor uptake, recycling and degradation).
At least 3 tumour suppressor pathways - TGF-b, MAD1, and menin / MEN1 - all of which are involved in human cancer, down-regulate expression of telomerase reverse transcriptase (TERT) : their mutations can lead to telomerase up-regulation in tumours without amplification or mutation in telomerase gene
• benign or innocent tumor : one that lacks the properties of invasion and metastasis and that is usually surrounded by a fibrous capsule; its cells also show a lesser degree of anaplasia than those of malignant tumors
• primary cancer / malignant tumor : EGFR overexpression initially cause caveolin 1 (CAV1)-dependent internalization of E-cadherin (which blocks tumor cell invasion by both adhesive-dependent and adhesive-independent (STP) mechanisms) on epithelial cells and ultimately reduces CAV1 protein levels, which activates the b-catenin signalling pathway and downregulates E-cadherin and CAV1 expression via SNAIL transcription factor and upregulates c-MYC via TCF/LEF1^ref. In response to EGF, EGFR-overexpressing cancer cells undergo an epithelial-mesenchymal transition, which is caused by loss of cell-cell junctions and cell depolarization. Laminin receptor 1 (whose STP leads to expression of type IV collagenase (72 kDa / MMP2 and 92 kDa / MMP9), which degrades basement membrane allowing tumor cell migration) is upregulated.
• cellular tumor : a tumor made up chiefly of cells in a homogeneous stroma.
• cystic tumor / cystoma : a tumor that contains cysts; specific types often have the prefixes cyst- or cysto-.
• neuroendocrine cell tumor : any of a diverse group of tumors containing neurosecretory cells that cause endocrine dysfunction; most are carcinoids or carcinomas. They occur most often in the gastrointestinal tract, in bronchial and tracheal mucous membranes, and in teratoid ovarian tumors.
• functional or functioning tumor : a hormone-secreting tumor in an endocrine gland
• endocrine-active adenoma / hyperfunctional or hyperfunctioning adenoma : a pituitary adenoma that secretes excessive amounts of a hormone
• nonfunctional or nonfunctioning tumor : a tumor located in an endocrine gland but not secreting hormones
• endocrine-inactive adenoma / nonfunctional, nonfunctioning, nonsecreting or nonsecretory adenoma : a pituitary adenoma that does not secrete excessive amounts of any hormone; many null-cell adenomas are of this type
• heterologous or heterotypic tumor : one made up of tissue which differs from that in which it grows.
• homoiotypic or homologous tumor : a tumor which resembles the surrounding parts in its structure.
• histioid tumor : one which is formed of a single tissue resembling that of the surrounding parts.
• intermediate progression (local malignancy) : infiltrating cancer (basal cell carcinoma has low infiltrative power but high metastatising power). Malignant tumor : one that has the properties of invasion and metastasis and that shows a greater degree of anaplasia than do benign tumors
• late progression (systemic malignancy) : tumor metastases (after 10-20 years) (squamous cell carcinoma has high infiltrative power but low metastatising power).

Correlation of cell polarity to vessels and metastatic outcome :

	tumour size (cm3)	polarity (vessels)	cells in blood (per 4 mL)	cells in lung (per 40 HPF)	lung metastasis/section
metastatic MTLn3 mammary tumour	31.0 +/- 5.5	high	22.8 +/- 13.6	35.7 +/- 10.1	17.9 +/- 13.6
non-metastatic MTC mammary tumour	44.5 +/- 9	low	0.25 +/- 0.16	0.75 +/- 0.75	0
p value	< 0.4	-	< 0.002	< 0.003	< 0.003

Tumour size is unrelated to metastasis, whereas carcinoma-cell polarity towards vessels is correlated with increased lung metastasis^ref.
Regulation of metastasis :
• tumour cells :
• facilitation of metastasis :
• production of growth factors and their receptors
• prodution of angiogenic factors
• motility, invasiveness
• Hsp90a is necessary for extracellular maturation of MMP2, promoting the migration of cancer cells through the extracellular protein meshwork^ref.
• aggregation, deformability
• specific cell-surface receptors and adhesion molecules
• anoikis has been suggested to act as a physiological barrier to metastasis; resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitating secondary tumour formation in distant organs. TrkB is a potent and specific suppressor of caspase-associated anoikis of non-malignant epithelial cells^ref
• inhibition of metastasis
• antigenicity
• inhibitors of angiogenesis
• cohesion (E-cadherin)
• tissue inhibitors of proteolytic enzymes
• host cells
• facilitation of metastasis
• paracrine and endocrine growth factors
• neovascularization
• platelets and their products
• immune cells and their products
• inhibition of metastasis
• tissue barriers
• blood turbulence, endothelial cells
• tissue inhibitors of proteolytic enzymes
• antiproliferative factors
• inhibitors of angiogenesis
Primary epithelial tumor metastasis requires cells to switch from a 2-D environment to proliferating at accelerated rates within the dense 3-D extracellular matrix (ECM) composed largely of type I collagen and cross-linked fibrin : 3-D growth of neoplastic and accessory cell populations are regulated by MT-MMP family members, expecially MMP-1, MMP2, and MMP-3. For some tumour cells, invasion is only blocked when both proteolysis and RHO-ROCK signalling (necessary and sufficient for a round morphology) are inhibited. Secreted protein, acidic and rich in cysteine (SPARC) / osteonectin is expressed by various tumour and stromal cells : expression by the latter helps to organize the basement-membrane structure that is required for tumour progression (angiogenesis and stromal "shield" that protects the tumour from immune-cell infiltration). It binds to components of the ECM such as fibrillar collagen and collagen type IV^ref. Ezrin / villin 2 and the homeoprotein transcription factor Six1 are highly expressed in metastatic tumours^ref.
Promigratory factors of the tumour microenvironment :
• chemokines :
• autocrine motility factor (AMF) in melanoma induces activation of migration through heterotrimeric G-proteins, PIPs, RAC and RHO^ref
• CXCL4 / SDF1 in ovarian cancer induces activation of migrationthrough heterotrimeric G-proteins, PI3K and RHO/ROCK^ref
• growth factors :
• EGF
• ovarian cancer : activation of autocrine signalling loops at the leading edge that induce ruffling and focal contact formation^ref
• breast cancer : activation of PI3K and PLC^ref
• LPA : activation of migration through heterotrimeric G-proteins and RHO/ROCK
• ovarian cancer^ref
• hepatocellular carcinoma (HCC)^ref
• IGF-1
• breast cancer : engagement of a₂b₁ integrin^ref and actrivation migration through PI3K, FAK and paxillin^ref
• pancreatic cancers, melanoma^ref : activation of PLCg, PI3K, RAC and RHO; facilitated detachment through activation of phosphatases
• partially degraded collagen : collagenases (MMP-1, MMP-13, MMP-14 / MT1-MMP) : engagement of a_vb₃ and a₂b₁ integrins
• factors that cleave laminin-5 (g₂ chain) :
• breast cancer cells : engagement of a_v integrins^ref
• melanoma : relase of chemotactic peptide^ref
TGF-b signalling really can switch from being tumour suppressive to pro-metastatic within a single cell lineage and this switch can be initiated by a single oncogenic events^ref. ERBB2 (expressed in 80% of DCIS) and TGF-b cooperate to cause invasion and migration MCF10A breast cancer cells^ref.
Inhibitors of metastases are lost in metastatic tumour clones :
• RAF kinase inhibitor protein (RKIP) inhibits RAF-mediated signalling
Routes of metastatization :
• lymphatic or lymphogenous metastases : from carcinomas (which have no lymph vessels in their stroma) via lymph vessels of surrounding normal tissue (eventually occluded by intralymphatic proliferation) => subcapsular sinuses of one or more lobules => proliferation and overwhelming of normal lymph nodal structure => hilus => efferent lymphatics. Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium^ref. Obstructed efferent lymph vessels may cause inversion of lymph flow metastases in abnormal locations (e.g. left supraclavear lymph nodes in gastric carcinoma when the thoracic dut is obstructed before joining the left succlavian vein). Shunts with blood vessels may cause paradoxical haematogenous metastases. Metastases in small capsular lymph node vessels only is named micrometastasis. Differential diagnosis with sinus histiocytosis, which is a reactive phenomenon to tumour antigens and has favorable prognostic meaning.

Laboratory examinations : sentinel lymph node (SLN) : the first lymph node to receive drainage from a tumor; used to determine whether there is lymphatic metastasis in certain types of cancer
• preoperative lymphoscintigraphy requires the administration of the ^99mTc-radiolabelled sulphur colloid (Nanocis) around the tumour
• intraoperative hand-held gamma probe detection requires the administration of the ^99mTc-radiolabelled sulphur colloid (Nanocis) around the tumour
• injection of the patent blue dye during the surgery of the sentinel node because of the dye uptake becomes visible
Following detection, the sentinel lymph node can be removed separately (sentinel lymph node biopsy (SLNB), a minimally invasive alternative to routine axillary dissection) and assessed with ultrastaging and IHC staining. The pathological status of the sentinel node should reflect the histopathology of the entire regional lymph drainage area and negative sentinel node may predict tumour-free regional nodes as skip metastases are exceedingly rare. Intradermal, periareolar one-site injection is superior to peritumoral 4-sites injections ^99mTc-sulphur colloid and single intradermal injection of bluedye over the tumour in sentinel lymph node identification. SLN is routinely assessed in :
• breast cancers
• melanoma
• colon cancers
• rectal cancers
• anal cancers
• uterine cervix cancers
• vulvar cancers
Quantum dots (QDs) are fluorescent crystals that are typically < 50 nm in diameter and have potential for many biological applications. QDs that fluoresce in the near-infrared (NIR) region of the spectrum overcome the problem of poor sensitivity and poor resolution of visible QDs or coventional organic fluorescent dyes in vivo. QDs 15.8 nm in diameter are well within the range that is required for retention in the SLN and when coated with polydentate phosphine they are made water soluble. NIR dots seem to photobrighten slightly. They are also stable in 100% serum at 37°C for > 30', indicating that they will survive prolonged exposure to bodily fluids at core body temperature. NIR QDs enter the lymphatic system and migrate quickly to the SLN when injected intradermally in mice, as confirmed by reinjection with the standard SLN mapping agent, isosulfan blue, and by histological examination. Real time imaging allows a surgeon to follow the lymphatic flow and quickly identify the SLN, so minimizing incision inaccuracies. Because the NIR QDs are stable and the fluorescence is intense, the surgeon can easily see the SLN throughout the biopsy procedure and can also inspect the surgical site to ensure total resection of the node. The next important step will be to examine the toxicity of the NIR QDs, as they contain 3 metals, which in their uncomplexed elemental forms cause acute and chronic toxicity. The current experiments - with very low doses of the complexed metals - did not reveal any short-term toxicity^ref.
Progressive vascular changes in a transgenic mouse model of squamous cell carcinoma : a sequence recognized the vasculatore in dysplastic skin but not in carcinomas is identical to that found in a loop of kallikrein-9, so it might bind to a substrate of this protease that is specifically expressed in the developing tumour vasculature^ref. 3 peptides (from PGDFs, WNTs, collagen XII, FGFR1 and TIE1) home specifically to angiogenic islets and colocalize with markers that identify endothelial cells and pericytes^ref.
• hematogenous metastases (canceremia : the presence of cancer cells in the blood) :
• via lymph flowing from thoracic duct into left succlavian vein
• via basement membrane digestion and diapedesis into capillaries, venules and arterioles (eventually causing tumor embolism). The endothelial dysfunction at the entry site (decreased PGI₂ incretion) and PGE₂ secretion by tumor cells trigger formation of a microthrombus
• direct metastasis : metastasis in the direction of the blood stream
• paradoxical or retrograde metastasis : metastasis taking place in a direction opposite to that of the blood stream
Metastasizing tumor cells grab onto P selectin on platelets and use them as a protective shield against immune system cells. Heparin treatment, which has been used with mixed success as part of chemotherapy, dramatically slows tumor metastasis by binding to P selectin on platelets before cancer cells can do the same. The response is inconsistent, however, perhaps because the chemical makeup of heparin is variable, and the clotting problems that can result from heparin therapy make it unlikely that heparin will be widely used as a chemotherapy agent. Other P selectin inhibitors may fare better, however.
Neoplastic cells into the thrombus can proliferate or undergo reproductive latency (dormient neoplastic cells).
Walther classification of haematogenous metastases :
• portal-type
• cava vein-type
• pulmonary type
Exceptions can be explained by arterovenous shunts or anastomoses between the portal and cava veins.
There is evidence that primary tumour cells can reprogramme their response to TGF-b, turning this tumour suppressor into a metastasis-inducing factor, while impairing tumour growth. Tropism depends on which receptors are expressed on both the metastatizing cancer cells and the endothelium of the recipient organs : chemokine receptors expressed on tumour cells and chemokines secreted by target organs have a critical role in determining the metastatic destination of tumour cells. Even the timing of tumour cell entry into the bloodstream can be crucial to the localization of metastases : even in hormone-independent cell-lines, blood flow to the ovaries increases during metestrus (when progesterone levels are high) and decreases during proestrus (when oestrogen levels are high), indicating differential delivery of the cancer cells to the ovaries. Alternatively, differential support of growth in the ovaries at different stages of oestrous might occur because of hormone-induced gene expression. Tracking metastatic tumor cell extravasation with quantum dots (QDs) nanocrystals and fluorescence emission-scanning microscopy^ref.
The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Bone marrow-derived haematopoietic progenitor cells that express VEGFR1 home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1⁺ cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3-competent VEGFR1⁺ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. VEGFR1⁺ cells express VLA-4 (also known as integrin a₄b₁), and that tumour-specific growth factors upregulate fibronectin—a VLA-4 ligand—in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1⁺ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1⁺VLA-4⁺ clusters dictate organ-specific tumour spread^ref
• contiguity metastases, e.g.
• lip cancers from one lip to the other
• oral cavity cancers (from cheek to gingiva)
• liver cancers from pancreatic head cancers
• iatrogenic metastases during surgery (in scar or elsewhere)
• transserosal or transcoelomatic metastases in
• mesotheliomas
• pericardial metastases
• peritoneal metastases
• pleural metastases
• intracanalicular metastases along direction of the flow (bolus flow, air flow, urinary flow, CSF flow)
• gastrointestinal tract (including biliary and pancreatic ducts)
• respiratory tract
• genitourinary tract
• ventricular system
A micrometastasis is an undetectable spread of cancer cells from the primary tumor to distant sites where they form microscopic secondary tumors that are not seen on routine screening tests, i.e. metastasis is too limited to have created enough mass to be observed.
A biochemical metastasis is the transportation and induction of abnormal immunochemical specificities in apparently normal organs.
The biological age of a tumour can be estimated from the number of chromosomal aberrations it contains, so a similar pattern of aberrations would be expected in metastases if cells migrate late in tumorigenesis : anyway M0 cells migrate far earlier than previously thought, and accumulate the changes that generate the secondary tumour over time, which explains the long latency period.
Magnetic resonance imaging (MRI) in conjunction with lymphotropic superparamagnetic nanoparticles (with a superparamagnetic iron oxide core that can be detected by MRI surrounded by a dense packing of dextrans that allows maintenance of nanoparticles in the circulation) is a useful non-invasive mean with 100% sensitivity (vs. 45% of standard MRI) and 96% specificity at identifying lymph nodes that contain metastatic tumours even < 2 mm in diameter : the particles circulate and accumulate in the lymph nodes. In normal lymph nodes, this signal eventually decreases as the particles are taken up by macrophages. In lymph nodes that contain metastases, however, there is either a limited decrease in signal intensity, or discrete focal defects within the node, due to replacement of nodal architecture by the tumour.
• multicentric, polycentric or synchronous disease : multiple primary tumours of the same histotype, usually with distance > 3 cm , e.g.
• most cancers caused by carcinogens acting over a long time on a wide surface
• multicentric hepatocellular carcinoma (HCC)
• multicentric bladder cancers
• multicentric breast cancers (> 5 cm or likely in different quadrants)
• most hereditary cancers
• multicentric Wilms' tumours
• multifocal or metachronous disease : multiple metastases from a single primary tumour within the same organ, usually with a distance < 3 cm, e.g.
• multifocal hepatocellular carcinoma (HCC)
• multifocal osteosarcoma
• multifocal breast cancers (likely within the same quadrant)
Localizations :
• bone metastases
• liver metastases
• cutaneous metastases
• brain metastases
• spinal metastases
• pericardial metastases
• peritoneal metastases
• pulmonary metastases
• pleural metastases
• adrenal gland metastases
• ovarian metastases
• breast metastases
Cancer cells don't normally express the chemokine receptors that are required for homing to target organs : renal cell carcinoma (RCC) cells acquire the ability to metastatize when hypoxia - characteristic of highly aggressive tumours - or mutation in VHL induces expression of CXCR4. In addition, tumour cells coud be primed to spread early in tumorigenesis by acquiring mutations in VHL.
Experimental animal models : Drosophilamelanogaster develop tumours, and despite some key differences from mammals - such as lack of vascular circulatory system - are becoming an important model system to study cancer. An assay begins with induction of non-.invasive tumour formation in the eye antennal disc/optic-lobe region (and do not spread beyond this region) using cells that express an activated form of Ras and GFP. The tumour cells are then mutagenized, through expression of the FLP recombinase, and flies are screened for mutants in which the GFP-labelled tumour cells have migrated to new tissues. Because Drosophila larvae are transparent, migration of fluorescent cells can be easily monitored. In one population of flies, the tumour cells migrated into the ventral nerve cord and eventually spread into the leg discs and tracheal vasculature. These tumour cells contained inactivating mutations in scribbled (human homolog SCRIB), which encodes a protein that regulates cell polarity and size. Cells with mutation in scrib alone, however, grow poorly in vivo and do not invade other tissues, indicating that a combination of Scrib inactivation and Ras activation are needed to cause metastatic behaviour^ref. Loss scrib in the larval eye imaginal disc -using FLP/FRT-mediated recombination - results in cells losing their columnar shape and monolayered morphology, to become more rounded and multilayered. However, as larval development progresses, the scrib- tissue is lost through apoptosis. This seems to be mediated through Jnk stress response. Although scrib homologues have not yet been shown to be tumour suppressors in humans, proteins that dictate cell polarity could be important in tumorigenesis^ref
Web resources :
• Cancer Invasion and Metastasis
• Cancer Metastasis
• transmission of cancer between individuals is extremely rare and has most often been reported to occur
• cancer à deux [Fr. “cancer in two”] : cancer attacking simultaneously or consecutively two persons who live together.
• in the setting of organ transplantation
• transplacental transmission of maternal malignancy to the fetus during pregnancy (different from transplacental transmission of cancer-causing infectious agents). Cancer is the second leading cause of death in women of reproductive age, and approximately 0.1% of pregnancies are affected by maternal malignancies. During metastatic spread of solid tumors or hematologic malignancies in the mother, tumor emboli may be localized in intervillous spaces, without being real placental metastasis. Rarely tumor emboli are able to invade the struma of chorionic villi and produce true placental metastases. There have been > 50 reported cases of maternal malignancies with metastases to the placenta and 14 cases with documented maternal-to-fetal metastases by vertical, transplacental transmission over the last 136 years. Most maternal malignancies diagnosed during pregnancy have a favorable outcome for both the mother and fetus, and pregnancy has not been shown to adversely influence patient outcome in the setting of these cancers. The fear of transplacental graft to the foetus is not an argument favorable of terminating a cancer associated pregnancy.


• An increased cancer risk due to prenatal exposure may be related to:
• exposure of the fetus during pregnancy to chemicals able to cross the placental barrier or to radiation. In transplacental carcinogenesis, the effects observed after birth are a consequence of a direct interaction of the carcinogen with somatic cells of the fetus. DES and radiation were shown to increase cancer risk in humans following exposure during pregnancy, while in experimental animals a large variety of chemicals of quite different structure (including the widely used therapeutic agent cisplatin) were demonstrated to induce tumors in the progeny after administration during pregnancy;
• exposure to a chemical or radiation of the parents or one parent prior to conception.
The experimental multigeneration effect of carcinogens is manifested in an increased incidence of tumors in several generations of untreated descendants of :
• females exposed to carcinogen during pregnancy;
• males exposed to carcinogen prior to mating with untreated females.
The inherited change may be an initiating event revealed by the exposure during post-natal life to a promoting agent. Thus the inherited predisposition to cancer that is observed today may, at least in part, be explained by the exposure to environmental noxious agents in previous generation(s)

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