Enzymes may cause mets!?

Clinical and Experimental Metastasis

May 1992, Volume 10, Issue 3, pp 145-155

The role of proteolytic enzymes in cancer invasion and metastasis

M.J. Duffy

The production of metastasis appears to involve a number of different
proteases including the urokinase form of plasminogen activator, cathepsin
B, cathepsin D and various metalloproteases. Early data implicating these
proteases in metastasis were mostly indirect and based on correlation
studies in animal models. More recent work, using specific protease
inhibitors and antibodies against proteases to block experimental
metastasis, have provided more direct evidence that proteases play a role in
cancer spread. In addition, transfection of genes encoding certain proteases
increases the metastatic phenotype of the recipient cells. In human tumours,
a number of different proteases also correlate with metastatic potential. It
is concluded that certain proteases may be new prognostic markers in cancer
as well as new targets for anti-metastatic therapy.

Cancer Res.1984 Feb;44(2):744-52.

Biochemical methods for predicting metastatic ability of prostatic cancer
utilizing the dunning R-3327 rat prostatic adenocarcinoma system as a model.

Lowe FC, Isaacs JT

Abstract

At present, there is no established diagnostic method by which the
metastatic ability of an individual prostatic cancer can be accurately
predicted. Metastasis is a multistep process, the first critical step of
which is invasion. Tumor invasion has been suggested to involve a variety of
hydrolytic enzyme activities; therefore, the tumor levels of these
activities might be indicative of the overall metastatic ability of the
cancer. In order to evaluate if the quantitative levels of hydrolytic
enzymes can be used to predict the metastatic ability of individual
prostatic cancers, five different Dunning R-3327 rat prostatic
adenocarcinoma sublines, with widely varying metastatic abilities, were
assayed for the respective levels of a variety of hydrolytic enzyme
activities (collagenase, trypsin-like, cathepsin B, neutral protease,
N-acetyl-beta-glucosaminidase, chymotrypsin-like, leucine aminopeptidase,
elastase, and plasminogen activator). These studies demonstrated that most
hydrolytic activities are not elevated when going from normal prostate to
prostatic cancer. In addition, only the levels of elastase and
chymotrypsin-like activity were found to be consistently higher in highly
metastatic prostatic cancers than in either the normal prostate or
low-metastatic prostatic cancers. It was found that, by combining the
relative activities of elastase and chymotrypsin-like activity and then
dividing by the relative activities of N-acetyl-beta-glucosaminidase, a
biochemical metastatic index could be constructed which accurately reflected
the respective metastatic ability of the Dunning sublines.

PMID:

6537899

[PubMed - indexed for MEDLINE]

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Trypsin, chymotrypsin and cancer

Hereditary pancreatitis carries a 40% risk of pancreatic cancer (5% risk
for non-hereditary pancreatitis), a very invasive cancer with high mortality
rates. Pancreatic inflammation promotes intensive cell proliferation to
regenerate the damaged pancreas, during which the amplification of
pathological changes in DNA can occur.

Elevated levels of trypsin have been found in a variety of other tumours,
such as ovarian and colorectal carcinomas, where it may have a role in
malignant tumour formation or metastasis. Trypsins appear to be necessary
for cancer cells to invade normal tissue, and to enter the bloodstream and
lymphatic channels. A critical step in cancer metastasis involves breaking
down the extracellular matrix surrounding the malignant tumour, which allows
it to invade and spread. Type I collagen degradation involves the action of
matrix metalloproteases (MMP-1, -8 and -13), which are activated by MMP-3.
Trypsin-2 can directly activate all four pro-MMP enzymes, and can degrade
type I collagen, acting as a potent tumour-associated matrix serine
protease. The inhibitor TATI (tumour-associated trypsin inhibitor) can
inhibit trypsin activation of pro-MMPs and trypsin degradation of type I
collagen. Not surprisingly, TATI has been detected at elevated levels in a
variety of tumours and in the serum of cancer patients. Trypsin has also
been shown to activate a G protein-coupled receptor PAR-2
(protease-activated receptor-2) in both colon and pancreatic cancer cell
lines, where it appears to act as a potent mitogen in vitro, functioning as
a growth factor.

Certain protease inhibitors appear to be capable of suppressing
carcinogenesis in a variety of model systems, the most potent of which
appear to inhibit chymotrypsin or chymotrypsin-like proteases. Both
soybean-derived BBI (inhibits trypsin and chymotrypsin) and human
alpha1-antichymotrypsin are potent inhibitors of chymotrypsin, are highly
anti-inflammatory, and may be involved in defence of their respective
organisms. BBI was found to help suppress a variety of tumours in different
organisms, both in vitro and in vivo. Extracts high in proteolytic enzymes,
especially trypsin, chymotrypsin and papain, have also been used in cancer
studies. Enzyme therapy appears to be anti-inflammatory by its induction of
protease inhibitors.

Experimental Oncology

British Journal of Cancer (1990) 62, 607-613. doi:10.1038/bjc.1990.339
Published October 1990

Serine protease-induced enhancement of blood-borne metastasis of rat ascites
tumour cells and its prevention with deoxyribonuclease

S Sugihara1
< http://www.nature.com/bjc/journal/v62/n4/abs/bjc1990339a.html#aff1> , T
Yamamoto, J Tsuruta, J Tanaka, T Kambara, T Hiraoka and Y Miyauchi

1First Department of Surgery, Kumamoto University Medical School, Japan

Abstract

Serine proteases, such as alpha-chymotrypsin or elastase, caused an
aggregation of rat ascites tumour cell lines, AH-130, AH-109A and YS, in a
protein free medium which preserved the cell viability. This aggregation,
which was monitored spectrophotometrically, was dependent upon the protease
activities and was resistant to treatment with either a calcium chelating
reagent (EDTA) or neuraminidase. However, the tumour cell aggregates were
redispersed by treatment with deoxyribonuclease I (DNase I). This dispersal
effect was dependent upon the DNase activity. A possible relationship
between the tumour cell aggregation and development of blood-borne
metastasis was studied. An intravenous inoculation in rats of tumour cell
aggregates performed by the alpha-chymotrypsin treatment resulted in
significantly higher numbers of lung metastatic foci than an injection of
single cells. When the re-separated single cells, prepared in vitro by
treatment with DNase I following alpha-chymotrypsin treatment, were injected
instead of the aggregates, the enhancement of metastasis was reversed. These
enhancement and reversal effects were mimicked in vivo by intravenous
injections of protease and nuclease following inoculation of a single cell
suspension. That is, the number of metastatic foci caused by single cell
inoculation followed by an intravenous alpha-chymotrypsin injection, was
higher than that in a control group receiving PBS [phosphate buffered
saline] instead of alpha-chymotrypsin. Again, this augmentation was reversed
by an injection of DNase I following alpha-chymotrypsin injection.
Furthermore, an injection of DNase I alone itself reduced the starting
number of metastases resulting from injection of the single tumour cell
suspension. These data suggest that the metastatic behaviour of tumour cells
may be increased by protease inducible DNA dependent cell aggregation should
it occur in the blood stream.

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I know...i am just as confused.

I know...Gonzalez enzyme therapy is very successful and based on pancreatin...who knows.