Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum

Table 1 General overview molecules/molecular pathways involved in the peritoneal metastatic cascade

Steps peritoneal metastatic cascade	Molecules/molecular pathways
Detachment from the primary tumor	Spontaneous tumor cell shedding:
	E-cadherin ↓
	N-cadherin ↑
	EMT
	PC1 and PC2 ↑
	Interstitial fluid pressure ↑
	Peroperative seeding tumor cells during surgery
Peritoneal transport	Muscinous ascites
	Actin microfilament system
	Lammelipodia, filipodia
Attachment to distant peritoneum	Transmesothelial dissemination:
	ICAM-1 ↑, PECAM-1, VCAM-1 ↑
	TNF-α, IL-1β, IL-6, IFN-γ
	β1 integrin subunit
	CD43, CD44
	Hyaluronan
	Translymphatic dissemination:
	Lymphatic stomata
	Milky spots
Invasion into the subperitoneal space	Rounding of mesothelial cells:
	HGF/SF ↑
	c-Met ↑
	Destruction of the mesothelial monolayer:
	Tumor-induced apoptosis
	Fas ligand/Fas
	Adherence to the basement membrane:
	Integrines
	Invasion of the peritoneal-blood barrier:
	MMP-1, MMP-2, MMP-7, MMP-9, MMP-13, MMP-14 ↑
	TIMP-1, TIMP-2, TIMP-3, TIMP-4
	uPA/uPAR
	plasminogen activator inhibitor -1 and -2
Proliferation and angiogenesis	Proliferation:
	EGFR, EGF, TGFα
	IGF-1, IGF-Binding Protein-3
	Angiogenesis:
	HIF-1α, HIF-1β
	VEGF/VEGFR

E-cadherin: Epithelial-cadherin; N-cadherin: Neural-cadherin; EMT: Epithelial to mesenchyme transition; PC: Polycystin; ICAM: Intercellular adhesion molecule-1; PECAM: Platelet-endothelial cell adhesion molecule-1; VCAM-1: Vascular adhesion molecule-1; TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; IL-6: Interleukin-6; IFN-γ: Interferon-γ; CD43: Sialophorin; HGF: Hepatocyte growth factor; SF: Scatter factor; MMP: Matrix metalloproteinases; TIMP: Tissue inhibitor metalloproteinases; uPA: Urokinase plasminogen activator; uPAR: Urokinase plasminogen activator receptor; EGFR: Epidermal growth factor receptor; EGF: Epidermal growth factor; TGFα: Tumor growth factor α; IGF-1: Insulin like growth factor-1; HIF: Hypoxia inducible factor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.

Table 2 Intra-operative peritoneal lavage: detection method, timing and outcome data

Ref.	Patients, n	Method of detection	Peritoneal lavage fluid	Timing of sampling	Intraperitoneal free cancer cells
Kirstensen et al[73]	237	PCR	200-600 mL 0.9% NaCl	After	8.01%
Nishikawa et al[74]	410	Cytology	200 mL 0.9% NaCl	Before	7.60%
Lloyd et al[75]	125	Immunobead RT-PCR	100 mL 0.9% NaCl	Before	12.80%
				After	29.60%
Bae et al[76]	145	Cytology	100 mL 0.9% NaCl	Before	4.10%
Noura et al[77]	697	Cytology	100 mL 0.9% NaCl	Before	2.20%
Altomare et al[79]	29	Thin-Prep	150 mL 0.9% NaCl	Before	13.80%
				After	2.60%
		RT-PCR	150 mL 0.9% NaCl	Before	37.90%
				After	41.40%
Rossi Del Monte et al[78]	48	Cytology	250 mL 0.9% NaCl	Before	0.00%
		Immunofluorescence	250 mL 0.9% NaCl	Before	17.00%
		qRT-PCR	250 mL 0.9% NaCl	Before	42.00%

PCR: Polymerase chain reaction; RT-PCR: Real-time polymerase chain reaction; qRT-PCR: Quantitative real-time polymerase chain reaction.

Table 3 Overview matrix metalloproteinases[124]

MMP	Name	Producing Cells	Substrates
MMP-1	Collagenase	Fibroblasts, synovial cells, chondrocyte	Collagen I, II, III, X
MMP-2	Gelatinase	Fibroblasts, chrondrocyte, mesangium	Gelatin, collagen IV, V, VII, XI
		endothelial cells, cancer cells	Laminin, fibronectin, elastin
MMP-3	Stromelysin-1	Synovial cells, chondrocyte, fibroblasts	Proteoglycan, collagen III, IV, VII, IX, elastin
MMP-7	Matrilysin	Cancer cells, macrophage	Proteoglycan, gelatin, fibronectin
			elastin, collagen IV, laminin
MMP-8	Neutrophil, Collagenase	Neutrophil	Collagen I, II, III
MMP-9	Gelatinase B	Neutrophil, macrophage, thromboblast	Gelatin, collagen III, IV, V
		osteoclast, cancer cells, T-lymphocyte	α2 chain, Elastin
MMP-10	Stromelysin-2	Cancer cells, T-lymphocyte	Collagen III, IV, V, fibronectin, gelatin
MMP-11	Stromelysin-3	Cancer cells, macrophage, mesangium	Fibronectin, laminin, proteoglycan, gelatin
MMP-12	Metalloestelase	Macrophage	Elastin
MMP-13	Collagenase-3	Chondrocyte, cancer cells	Collagen I, II, III
MMP-14	MT1-MMP	Cancer cells, fibroblasts	Collagen I, II, III, gelatin, Laminin
			Fibronectin, vitronectin, proteoglycan
MMP-15	MT2-MMP	Cancer cells, fibroblasts	Fibronectin, aggrecan, tenascin
MMP-16	MT3-MMP	Neuronal cell	Collagen III, gelatin, fibronectin
MMP-17	MT4-MMP	Unknown	Unknown
MMP-20	Enamelysin	Odontoblast	Amelogenin, gelatin
MMP-24	MT5-MMP	Unknown	Unknown
MMP-25	MT6-MMP	Unknown	Unknown
TIMP-1		Tissue, extracellular fluid	Complex formation with pro-MMP-9 and MMPs
TIMP-2		Tissue, extracellular fluid	Complex formation with pro-MMP-9, inhibition of MMP-2 degradation

MMP: Matrix metalloproteinases; TIMP: Tissue inhibitor metalloproteinases.